US20230364199A1 - Improvement of physical and mental well-being of patients with hypoparathyroidism - Google Patents

Improvement of physical and mental well-being of patients with hypoparathyroidism Download PDF

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US20230364199A1
US20230364199A1 US18/028,989 US202118028989A US2023364199A1 US 20230364199 A1 US20230364199 A1 US 20230364199A1 US 202118028989 A US202118028989 A US 202118028989A US 2023364199 A1 US2023364199 A1 US 2023364199A1
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Kennett Sprogøe
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Ascendis Pharma Bone Diseases AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

  • the present invention relates to a sustained-release PTH compound for use in a method of improving and treating the physical and mental well-being of patients having hypoparathyroidism, wherein the sustained-release PTH compound releases PTH with a release half-life of at least 12 hours.
  • Hypoparathyroidism is a disorder characterized by hypocalcemia and absent or deficient PTH.
  • Standard treatment consists of oral calcium and vitamin D supplementation. This approach presents a therapeutic challenge, because large amounts of calcium and vitamin D are often required and attendant concerns about long term complications are often expressed.
  • Many patients with hypoparathyroidism complain of reduced quality of life (QoL).
  • Biochemical control with standard therapy is rarely accompanied by improved functioning or sense of well-being.
  • Complaints of cognitive dysfunction are common, with the term “brain fog” being typically used by patients to describe these symptoms.
  • the PTH1 receptor which is activated by both PTH and PTHrP
  • the PTH2 receptor which is activated by PTH and tuberoinfundibular peptide of 39 residues (TIP39)
  • TIP39 tuberoinfundibular peptide of 39 residues
  • sustained-release PTH compound for use in a method of improving and treating the physical and mental well-being of patients having hypoparathyroidism, wherein the sustained-release PTH compound releases PTH with a release half-life of at least 12 hours.
  • PTH refers to all PTH polypeptides, preferably from mammalian species, more preferably from human and mammalian species, more preferably from human and murine species, as well as their variants, analogs, orthologs, homologs, and derivatives and fragments thereof, that are characterized by raising serum calcium and renal phosphorus excretion, and lowering serum phosphorus and renal calcium excretion.
  • PTH also refers to all PTHrP polypeptides, such as the polypeptide of SEQ ID NO:121, that bind to and activate the common PTH/PTHrP1 receptor.
  • PTH refers to the PTH polypeptide of SEQ ID NO:51 as well as its variants, homologs and derivatives exhibiting essentially the same biological activity, i.e. raising serum calcium and renal phosphorus excretion, and lowering serum phosphorus and renal calcium excretion.
  • PTH refers to the following polypeptide sequences:
  • PTH refers to the following polypeptide sequences:
  • the term “PTH” refers to the sequence of SEQ ID:NOs 47, 48, 49, 50, 51, 52, 53, 54, 55, 107, 108, 109, 110, 111, 112, 113, 114 and 115. In certain embodiments the term “PTH” refers to the sequence of SEQ ID:NOs 50, 51, 52, 110, 111 and 112. In certain embodiments the term “PTH” refers to the sequence of SEQ ID NO:51.
  • PTH refers to the sequence of SEQ ID:NOs 122, 123, 124, 125, 126 and 127. In certain embodiments the term “PTH” refers to the sequence of SEQ ID NO: 122.
  • PTH refers to the sequence of SEQ ID:NOs 128, 129, 130 and 131. In certain embodiments the term “PTH” refers to the sequence of SEQ ID NO: 128.
  • PTH refers to the sequence of SEQ ID:NO: 132. In certain embodiments the term “PTH” refers to the sequence of SEQ ID NO: 133.
  • PTH polypeptide variant refers to a polypeptide from the same species that differs from a reference PTH or PTHrP polypeptide.
  • such reference is a PTH polypeptide sequence and has the sequence of SEQ ID NO:51.
  • differences are limited so that the amino acid sequence of the reference and the variant are closely similar overall and, in many regions, identical.
  • PTH polypeptide variants are at least 70%, 80%, 90%, or 95% identical to a reference PTH or PTHrP polypeptide, such as to the PTH polypeptide of SEQ ID NO:51.
  • polypeptide having an amino acid sequence at least, for example, 95% “identical” to a query amino acid sequence it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. These alterations of the reference sequence may occur at the amino (N-terminal) or carboxy terminal (C-terminal) positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
  • the query sequence may be an entire amino acid sequence of the reference sequence or any fragment specified as described herein, such as the sequence of SEQ ID NO:51.
  • PTH polypeptide variants may be naturally occurring variants, such as naturally occurring allelic variants encoded by one of several alternate forms of a PTH or PTHrP occupying a given locus on a chromosome or an organism, or isoforms encoded by naturally occurring splice variants originating from a single primary transcript.
  • a PTH polypeptide variant may be a variant that is not known to occur naturally and that can be made by mutagenesis techniques known in the art.
  • N-terminus or C-terminus of a bioactive polypeptide may be deleted from the N-terminus or C-terminus of a bioactive polypeptide without substantial loss of biological function.
  • Such N- and/or C-terminal deletions are also encompassed by the term PTH polypeptide variant.
  • PTH polypeptide also encompasses all PTH and PTHrP polypeptides encoded by PTH and PTHrP analogs, orthologs, and/or species homologs. It is also recognized by one of ordinary skill in the art that PTHrP and PTHrP analogs bind to activate the common PTH/PTHrP1 receptor, so the term PTH polypeptide also encompasses all PTHrP analogs.
  • PTH analog refers to PTH and PTHrP of different and unrelated organisms which perform the same functions in each organism but which did not originate from an ancestral structure that the organisms' ancestors had in common.
  • analogous PTH and PTHrP arose separately and then later evolved to perform the same or similar functions.
  • analogous PTH and PTHrP polypeptides are polypeptides with quite different amino acid sequences but that perform the same biological activity, namely raising serum calcium and renal phosphorus excretion, and lowering serum phosphorus and renal calcium excretion.
  • PTH ortholog refers to PTH and PTHrP within two different species which sequences are related to each other via a common homologous PTH or PTHrP in an ancestral species, but which have evolved to become different from each other.
  • PTH homolog refers to PTH and PTHrP of different organisms or artificial PTH sequences which perform the same functions and which originate from an ancestral structure that the organisms' ancestors had in common.
  • homologous PTH polypeptides are polypeptides with quite similar amino acid sequences that perform the same biological activity, namely raising serum calcium and renal phosphorus excretion, and lowering serum phosphorus and renal calcium excretion.
  • PTH polypeptide homologs may be defined as polypeptides exhibiting at least 40%, 50%, 60%, 70%, 80%, 90% or 95% identity to a reference PTH or PTHrP polypeptide, such as the PTH polypeptide of SEQ ID NO:51.
  • a PTH polypeptide according to the invention may be, for example: (i) one in which at least one of the amino acids residues is substituted with a conserved or non-conserved amino acid residue, preferably a conserved amino acid residue, and such substituted amino acid residue may or may not be one encoded by the genetic code; and/or (ii) one in which at least one of the amino acid residues includes a substituent group; and/or (iii) one in which the PTH polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol); and/or (iv) one in which additional amino acids are fused to the PTH polypeptide, such as an IgG Fc fusion region polypeptide or leader or secretory sequence or a sequence which is employed for purification of the above form of the polypeptide or a pre-protein sequence.
  • PTH polypeptide fragment refers to any polypeptide comprising a contiguous span of a part of the amino acid sequence of a PTH or PTHrP polypeptide, such as the polypeptide of SEQ ID NO:51.
  • a PTH polypeptide fragment comprises at least 6, such as at least 8, at least or at least 17 consecutive amino acids of a PTH or PTHrP polypeptide, such as of the polypeptide of SEQ ID NO:51.
  • a PTH polypeptide fragment may additionally be described as sub-genuses of PTH or PTHrP polypeptides comprising at least 6 amino acids, wherein “at least 6” is defined as any integer between 6 and the integer representing the C-terminal amino acid of a PTH or PTHrP polypeptide, preferably of the polypeptide of SEQ ID No:51.
  • PTH or PTHrP polypeptide fragments at least 6 amino acids in length, as described above, that are further specified in terms of their N-terminal and C-terminal positions.
  • PTH polypeptide fragment as individual species are all PTH or PTHrP polypeptide fragments, at least 6 amino acids in length, as described above, that may be particularly specified by a N-terminal and C-terminal position.
  • PTH also includes poly(amino acid) conjugates which have a sequence as described above, but having a backbone that comprises both amide and non-amide linkages, such as ester linkages, like for example depsipeptides.
  • Depsipeptides are chains of amino acid residues in which the backbone comprises both amide (peptide) and ester bonds.
  • side chain refers either to the moiety attached to the alpha-carbon of an amino acid moiety, if the amino acid moiety is connected through amine bonds such as in polypeptides, or to any carbon atom-comprising moiety attached to the backbone of a poly(amino acid) conjugate, such as for example in the case of depsipeptides.
  • PTH refers to polypeptides having a backbone formed through amide (peptide) bonds.
  • PTH includes the above-described variants, analogs, orthologs, homologs, derivatives and fragments of PTH and PTHrP, all references to specific positions within a reference sequence also include the equivalent positions in variants, analogs, orthologs, homologs, derivatives and fragments of a PTH or PTHrP moiety, even if not specifically mentioned.
  • C-terminally truncated PTH refers to PTH polypeptides having a C-terminal deletion of at least 35 consecutive amino acid based on the sequence of PTH 1-84 (SEQ ID NO:1) and to PTH polypeptides having such C-terminal deletion of at least 35 consecutive amino acids based on the sequence of PTH 1-84 with a homology of at least 90% to the respective amino acids of PTH 1-84.
  • the C-terminal deletion compared to PTH 1-84 is at most 50 amino acids.
  • sustained-release PTH compound refers to any compound, conjugate, crystal or admixture that comprises at least one PTH molecule or PTH moiety and from which the at least one PTH molecule or PTH moiety is released with a release half-life of at least 12 hours.
  • release half-life and “half-life” refer to the time required under physiological conditions (i.e. aqueous buffer, pH 7.4, 37° C.) until half of all PTH or PTH moieties, respectively, of a sustained-release PTH compound are released from said sustained-release PTH compound.
  • stable PTH compound refers to any covalent conjugate of at least one PTH moiety to another moiety, wherein the at least one PTH moiety is connected to said other moiety through a stable linkage.
  • the terms “improving the mental well-being” and “improving the physical well-being” mean a measurable improvement from baseline in a test measuring the QoL aspects of mental and physical well-being, such as the Short Form-36 (SF-36). In certain embodiments such improvement is statistically significant.
  • the SF-36 provides for both a Mental Component Summary (MCS) and a Physical Component Summary (PCS).
  • MCS Mental Component Summary
  • PCS Physical Component Summary
  • the minimum important difference (MID) in T-score is 2 points for PCS and 3 points for MCS.
  • MID minimum important difference
  • micelle means an aggregate of amphiphilic molecules dispersed in a liquid colloid. In aqueous solution a typical micelle forms an aggregate with the hydrophilic moiety of the surfactant molecules facing the surrounding solvent and the hydrophobic moiety of the surfactant molecule facing inwards, also called “normal-phase micelle”. “Invers micelles” have the hydrophilic moiety facing inwards and the hydrophobic moiety facing the surrounding solvent.
  • liposome refers to a vesicle, such as a spherical vesicle, having at least one lipid bilayer.
  • liposomes comprise phospholipids, such as phosphatidylcholine.
  • liposome refers to various structures and sizes, such as, for example, to multilamellar liposome vesicles (MLV) having more than one concentric lipid bilayer with an average diameter of 100 to 1000 nm, small unilamellar liposome vesicles (SUV) having one lipid bilayer and an average diameter of 25 to 100 nm, large unilamellar liposome vesicles (LUV) having one lipid bilayer and an average diameter of about 1000 ⁇ m and giant unilamellar vesicles (GUV) having one lipid bilayer and an average diameter of 1 to 100 ⁇ m.
  • LUV large unilamellar liposome vesicles
  • GUI giant unilamellar vesicles
  • the term “liposome” also includes elastic vesicles such as transferosomes and ethosomes, for example.
  • aquasome refers to spherical nanoparticles having a diameter of 60 to 300 nm that comprise at least three layers of self-assembled structure, namely a solid phase nanocrystalline core coated with an oligomeric film to which drug molecules are adsorbed with or without modification of the drug.
  • ethosome refers to lipid vesicles comprising phospholipids and ethanol and/or isopropanol in relatively high concentration and water, having a size ranging from tens of nanometers to micrometers.
  • LeciPlex refers to positively charged phospholipid-based vesicular system which comprises soy PC, a cationic agent, and a bio-compatible solvent like PEG 300, PEG 400, diethylene glycol monoethyl ether, tetrahydrofurfuryl alcohol polyethylene glycol ether or 2-pyrrolidoneor N-methyl-2-pyrrolidone.
  • nuclear refers to unilamellar or multilamellar vesicles comprising non-ionic surfactants.
  • pharmacosome refers to ultrafine vesicular, micellar or hexagonal aggregates from lipids covalently bound to biologically active moieties.
  • niosome refers to dry formulations of surfactant-coated carrier which on rehydration and mild agitation gives niosomes.
  • polymersome refers to an artificial spherical vesicle comprising a membrane formed from amphiphilic synthetic block copolymers and may optionally comprise an aqueous solution in its core.
  • a polymersome has a diameter ranging from 50 nm to 5 ⁇ m and larger.
  • syntosomes which are polymersomes engineered to comprise channels that allow certain chemicals to pass through the membrane into or out of the vesicle.
  • sphingosome refers to a concentric, bilayered vesicle in which an aqueous volume is entirely enclosed by a membranous lipid bilayer mainly composed of natural or synthetic sphingolipid.
  • transferosome refers to ultraflexible lipid vesicles comprising an aqueous core that are formed from a mixture of common polar and suitable edge-activated lipids which facilitate the formation of highly curved bilayers which render the transferosome highly deformable.
  • ufasome refers to a vesicle comprising unsaturated fatty acids.
  • polypeptide refers to a peptide comprising up to and including 50 amino acid monomers.
  • polypeptide For simplification, all PTH drugs and drug moieties are referred to as “polypeptide”, even if it is longer than 50 amino acids, such as for example the sequence of SEQ ID NO:1.
  • protein refers to a polypeptide of more than 50 amino acid residues.
  • a protein comprises at most 20000 amino acid residues, such as at most 15000 amino acid residues, such as at most 10000 amino acid residues, such as at most 5000 amino acid residues, such as at most 4000 amino acid residues, such as at most 3000 amino acid residues, such as at most 2000 amino acid residues, such as at most 1000 amino acid residues.
  • physiological conditions refers to an aqueous buffer at pH 7.4, 37° C.
  • the term “pharmaceutical composition” refers to a composition containing one or more active ingredients, such as for example at least one sustained-release PTH compound, and one or more excipients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients of the composition, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing one or more sustained-release PTH compound and a pharmaceutically acceptable excipient.
  • liquid composition refers to a mixture comprising water-soluble sustained-release PTH compound and one or more solvents, such as water.
  • composition relates to a mixture comprising water-insoluble sustained-release PTH compound and one or more solvents, such as water.
  • dry composition means that a pharmaceutical composition is provided in a dry form. Suitable methods for drying are spray-drying and lyophilization, i.e. freeze-drying. Such dry composition has a residual water content of a maximum of 10%, preferably less than 5% and more preferably less than 2%, determined according to Karl Fischer. In certain embodiments the pharmaceutical composition of the present invention is dried by lyophilization.
  • excipient refers to a diluent, adjuvant, or vehicle with which the therapeutic, such as a drug or prodrug, is administered.
  • Such pharmaceutical excipient can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water is an exemplary excipient when the pharmaceutical composition is administered orally.
  • Saline and aqueous dextrose are exemplary excipients when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are frequently employed as liquid excipients for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the pharmaceutical composition can also contain minor amounts of wetting or emulsifying agents, pH buffering agents, like, for example, acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or can contain detergents, like Tween, poloxamers, poloxamines, CHAPS, Igepal, or amino acids like, for example, glycine, lysine, or histidine.
  • pH buffering agents like, for example, acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid)
  • detergents like Tween, poloxamers, poloxamines, CHAPS, Igepal, or amino acids like, for example,
  • the pharmaceutical composition can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • Oral formulation can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions will contain a therapeutically effective amount of the drug or drug moiety, together with a suitable amount of excipient so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • the sustained-release PTH compound comprises one or more acidic or basic groups
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the sustained-release PTH compound comprising acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • the sustained-release PTH compound comprising one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the sustained-release PTH compound of the present invention simultaneously comprise acidic and basic groups
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these compounds with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable means a substance that does cause harm when administered to a patient and in particular means approved by a regulatory agency, such as the EMA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably for use in humans.
  • a regulatory agency such as the EMA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably for use in humans.
  • drug refers to a substance, such as PTH, used in the treatment, cure, prevention, or diagnosis of a disease or used to otherwise enhance physical or mental well-being. If a drug is conjugated to another moiety, the moiety of the resulting product that originated from the drug is referred to as “drug moiety”.
  • prodrug refers to a conjugate in which a drug moiety is reversibly and covalently connected to a specialized protective group through a reversible linker moiety, also referred to as “reversible prodrug linker moiety”, which comprises a reversible linkage with the drug moiety and wherein the specialized protective group alters or eliminates undesirable properties in the parent molecule. This also includes the enhancement of desirable properties in the drug and the suppression of undesirable properties.
  • the specialized non-toxic protective group is referred to as “carrier”.
  • a prodrug releases the reversibly and covalently bound drug moiety in the form of its corresponding drug.
  • a prodrug is a conjugate comprising a drug moiety which is covalently and reversibly conjugated to a carrier moiety via a reversible prodrug linker moiety, which covalent and reversible conjugation of the carrier to the reversible prodrug linker moiety is either directly or through a spacer.
  • Such conjugate releases the formerly conjugated drug moiety in the form of a free drug.
  • reversible prodrug linker moiety is a spacer moiety that connects a drug moiety, such as a PTH moiety, to a carrier moiety, either directly or through a further spacer moiety and wherein the linkage between the reversible prodrug linker moiety and the drug moiety is reversible.
  • the linkage between the carrier moiety and the reversible prodrug linker moiety is a stable.
  • a “biodegradable linkage” or a “reversible linkage” is a linkage that is hydrolytically degradable, i.e. cleavable, in the absence of enzymes under physiological conditions (aqueous buffer at pH 7.4, 37° C.) with a half-life ranging from 12 hours to three months, in certain embodiments from 24 hours to two months, in certain embodiments from 30 hours to 6 weeks, in certain embodiments from 36 hours to one month, and in certain embodiments from 48 hours to three weeks.
  • a “stable linkage” is a linkage having a half-life under physiological conditions (aqueous buffer at pH 7.4, 37° C.) of more than three months.
  • traceless prodrug linker means a reversible prodrug linker, i.e. a linker moiety reversibly and covalently connecting the drug moiety with the carrier, which upon cleavage releases the drug in its free form.
  • free form of a drug means the drug in its unmodified, pharmacologically active form.
  • reagent means a chemical compound which comprises at least one functional group for reaction with the functional group of another chemical compound or drug. It is understood that a drug comprising a functional is also a reagent.
  • moiety means a part of a molecule, which lacks one or more atoms compared to the corresponding reagent. If, for example, a reagent of the formula “H—X—H” reacts with another reagent and becomes part of the reaction product, the corresponding moiety of the reaction product has the structure “H—X—” or “—X—”, whereas each “—” indicates attachment to another moiety. Accordingly, a drug moiety is released from a prodrug as a drug.
  • sequence or chemical structure of a group of atoms is provided which group of atoms is attached to two moieties or is interrupting a moiety, said sequence or chemical structure can be attached to the two moieties in either orientation, unless explicitly stated otherwise.
  • a moiety “—C(O)N(R 1 )—” can be attached to two moieties or interrupting a moiety either as “—C(O)N(R 1 )—” or as “—N(R 1 )C(O)—”.
  • a moiety “—C(O)N(R 1 )—” can be attached to two moieties or interrupting a moiety either as “—C(O)N(R 1 )—” or as “—N(R 1 )C(O)—”.
  • a moiety “—C(O)N(R 1 )—” can be attached to two moieties or interrupting a moiety either as “—C(O)N(R 1 )—” or as “—N(R 1
  • the term “functional group” means a group of atoms which can react with other groups of atoms.
  • Functional groups include but are not limited to the following groups: carboxylic acid, primary amine, secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamides, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, and aziridine.
  • the term “about” in combination with a numerical value is used to indicate a range ranging from and including the numerical value plus and minus no more than 10% of said numerical value, in certain embodiments no more than 8% of said numerical value, in certain embodiments no more than 5% of said numerical value and in certain embodiments no more than 2% of said numerical value.
  • the phrase “about 200” is used to mean a range ranging from and including 200+/ ⁇ 10%, i.e. ranging from and including 180 to 220; in certain embodiments 200+/ ⁇ 8%, i.e. ranging from and including 184 to 216; in certain embodiments ranging from and including 200+/ ⁇ 5%, i.e.
  • polymer means a molecule comprising repeating structural units, i.e. the monomers, connected by chemical bonds in a linear, circular, branched, crosslinked or dendrimeric way or a combination thereof, which may be of synthetic or biological origin or a combination of both. It is understood that a polymer may also comprise one or more other chemical groups and/or moieties, such as, for example, one or more functional groups. In certain embodiments a soluble polymer has a molecular weight of at least 0.5 kDa, e.g.
  • the polymer in certain embodiments has a molecular weight of at most 1000 kDa, such as at most 750 kDa, such as at most 500 kDa, such as at most 300 kDa, such as at most 200 kDa, such as at most 100 kDa. It is understood that for insoluble polymers, such as hydrogels, no meaningful molecular weight ranges can be provided. It is understood that also a protein is a polymer in which the amino acids are the repeating structural units, even though the side chains of each amino acid may be different.
  • polymeric means a reagent or a moiety comprising one or more polymers or polymer moieties.
  • a polymeric reagent or moiety may optionally also comprise one or more other moiety/moieties, which are preferably selected from the group consisting of:
  • the molecular weight ranges, molecular weights, ranges of numbers of monomers in a polymer and numbers of monomers in a polymer as used herein refer to the number average molecular weight and number average of monomers, i.e. to the arithmetic mean of the molecular weight of the polymer or polymeric moiety and the arithmetic mean of the number of monomers of the polymer or polymeric moiety.
  • any integer given for “x” therefore corresponds to the arithmetic mean number of monomers.
  • Any range of integers given for “x” provides the range of integers in which the arithmetic mean numbers of monomers lies.
  • An integer for “x” given as “about x” means that the arithmetic mean numbers of monomers lies in a range of integers of x+/ ⁇ 10%, such as x+/ ⁇ 8%, such as x+/ ⁇ 5% and in particular x+/ ⁇ 2%.
  • number average molecular weight means the ordinary arithmetic mean of the molecular weights of the individual polymers.
  • water-soluble with reference to a compound means that at least 1 g of such compound can be dissolved in one liter of water at 20° C. to form a homogeneous solution. Accordingly, the term “water-insoluble” with reference to compound means that less than 1 g of said compound can be dissolved in one liter of water at 20° C. to form a homogeneous solution.
  • hydrogel means a hydrophilic or amphiphilic polymeric network composed of homopolymers or copolymers, which is insoluble due to the presence of covalent chemical crosslinks.
  • the crosslinks provide the network structure and physical integrity.
  • thermogelling means a compound that is a liquid or a low viscosity solution having a viscosity of less than 500 cps at 25° C. at a shear rate of about 0.1/second at a low temperature, which low temperature ranges between about 0° C. to about 10° C., but which is a higher viscosity compound of less than 10000 cps at 25° C. at a shear rate of about 0.1/second at a higher temperature, which higher temperature ranges between about 30° C. to about 40° C., such as at about 37° C.
  • PEG-based in relation to a moiety or reagent means that said moiety or reagent comprises PEG.
  • a PEG-based moiety or reagent comprises at least 10% (w/w) PEG, such as at least 20% (w/w) PEG, such as at least 30% (w/w) PEG, such as at least 40% (w/w) PEG, such as at least 50% (w/w), such as at least 60 (w/w) PEG, such as at least 70% (w/w) PEG, such as at least 80% (w/w) PEG, such as at least 90% (w/w) PEG, such as at least 95%.
  • the remaining weight percentage of the PEG-based moiety or reagent are other moieties preferably selected from the following moieties and linkages:
  • PEG-based comprising at least X % PEG in relation to a moiety or reagent means that said moiety or reagent comprises at least X % (w/w) ethylene glycol units (—CH 2 CH 2 O—), wherein the ethylene glycol units may be arranged blockwise, alternating or may be randomly distributed within the moiety or reagent and in certain embodiments all ethylene glycol units of said moiety or reagent are present in one block; the remaining weight percentage of the PEG-based moiety or reagent may be selected from the following moieties and linkages:
  • hyaluronic acid-based comprising at least X % hyaluronic acid is used accordingly.
  • spacer moiety as used here in means any moiety that connects two other moieties.
  • a spacer moiety is selected from the group consisting of -T-, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T-, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R y2 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y3 )—, —S(O) 2 N(R y3 )—, —S(O)N(R y3 )—, —S(O) 2 —
  • substituted means that one or more —H atom(s) of a molecule or moiety are replaced by a different atom or a group of atoms, which are referred to as “substituent”.
  • the one or more further optional substituents are independently of each other selected from the group consisting of halogen, —CN, —COOR x1 , —OR x1 , —C(O)R x1 , —C(O)N(R x1 R x1a ), —S(O) 2 N(R x1 R x1a ), —S(O)N(R x1 R x1a ), —S(O) 2 R x1 , —S(O)R x1 , —N(R x1 )S(O) 2 N(R x1a R x1b ), —SR x1 , —N(R x1 R x1a ), —NO 2 , —OC(O)R x1 , —N(R x1 )C(O)R x1a , —N(R x1 )S(O) 2 R x1
  • each T 0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; wherein each T° is independently optionally substituted with one or more —R x2 , which are the same or different;
  • the one or more further optional substituents are independently of each other selected from the group consisting of halogen, —CN, —COOR x1 , —OR x1 , —C(O)R x1 , —C(O)N(R x1 R x1a ), —S(O) 2 N(R x1 R x1a ), —S(O)N(R x1 R x1a ), —S(O) 2 R x1 , —S(O)R x1 , —N(R x1 )S(O) 2 N(R x1a R x1b ), —SR x1 , —N(R x1 R x1a ), —NO 2 , —OC(O)R x1 , —N(R x1 )C(O)R x1a , —N(R x1 )S(O) 2 R x1
  • the one or more further optional substituents are independently of each other selected from the group consisting of halogen, —CN, —COOR x1 , —OR x1 , —C(O)R x1 , C(O)N(R x1 R x1a ), —S(O) 2 N(R x1 R x1a ), —S(O)N(R x1 R x1a ), —S(O) 2 R x1 , —S(O)R x1 , —N(R x1 )S(O) 2 N(R x1a R x1b ), —SR x1 , —N(R x1 R x1a ), —NO 2 , —OC(O)R x1 , —N(R x1 )C(O)R x1a , —N(R x1 )S(O) 2 R x1a
  • a maximum of 6 —H atoms of an optionally substituted molecule are independently replaced by a substituent, e.g. 5 —H atoms are independently replaced by a substituent, 4 —H atoms are independently replaced by a substituent, 3 —H atoms are independently replaced by a substituent, 2-H atoms are independently replaced by a substituent, or 1-H atom is replaced by a substituent.
  • interrupted means that a moiety is inserted between two carbon atoms or—if the insertion is at one of the moiety's ends—between a carbon or heteroatom and a hydrogen atom and in certain embodiments is inserted between a carbon and a hydrogen atom.
  • C 1 -4 alkyl alone or in combination means a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms. If present at the end of a molecule, examples of straight-chain or branched C 1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • C 1-4 alkyl groups are —CH 2 —, —CH 2 —CH 2 —, —CH(CH 3 )—, —CH 2 —CH 2 —CH 2 —, —CH(C 2 H 5 )—, —C(CH 3 ) 2 —.
  • Each hydrogen of a C 1-4 alkyl carbon may optionally be replaced by a substituent as defined above.
  • a C 1-4 alkyl may be interrupted by one or more moieties as defined below.
  • C 1-6 alkyl alone or in combination means a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. If present at the end of a molecule, examples of straight-chain and branched C 1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • C 1-6 alkyl groups are —CH 2 —, —CH 2 —CH 2 —, —CH(CH 3 )—, —CH 2 —CH 2 —CH 2 —, —CH(C 2 H 5 )— and —C(CH 3 ) 2 —.
  • Each hydrogen atom of a C 1-6 carbon may optionally be replaced by a substituent as defined above.
  • a C 1-6 alkyl may be interrupted by one or more moieties as defined below.
  • C 1-10 alkyl means an alkyl chain having 1 to 10, 1 to 20 or 1 to 50 carbon atoms, respectively, wherein each hydrogen atom of the C 1-10 , C 1-20 or C 1-50 carbon may optionally be replaced by a substituent as defined above.
  • a C 1-10 or C 1-50 alkyl may be interrupted by one or more moieties as defined below.
  • C 2-6 alkenyl alone or in combination means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon double bond having 2 to 6 carbon atoms. If present at the end of a molecule, examples are —CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —CH 2 —CH ⁇ CH 2 , —CH ⁇ CHCH 2 —CH 3 and —CH ⁇ CH—CH ⁇ CH 2 . When two moieties of a molecule are linked by the C 2-6 alkenyl group, then an example for such C 2-6 alkenyl is —CH ⁇ CH—.
  • Each hydrogen atom of a C 2-6 alkenyl moiety may optionally be replaced by a substituent as defined above.
  • a C 2-6 alkenyl may be interrupted by one or more moieties as defined below.
  • C 2-10 alkenyl means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon double bond having 2 to 10, 2 to 20 or 2 to 50 carbon atoms.
  • Each hydrogen atom of a C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 alkenyl group may optionally be replaced by a substituent as defined above.
  • a C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 alkenyl may be interrupted by one or more moieties as defined below.
  • C 2-6 alkynyl alone or in combination means straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon triple bond having 2 to 6 carbon atoms. If present at the end of a molecule, examples are —C ⁇ CH, —CH 2 —C ⁇ CH, CH 2 —CH 2 —C ⁇ CH and CH 2 —C ⁇ C—CH 3 .
  • an example is Each hydrogen atom of a C 2-6 alkynyl group may optionally be replaced by a substituent as defined above.
  • one or more double bond(s) may occur.
  • a C 2-6 alkynyl may be interrupted by one or more moieties as defined below.
  • C 2-10 alkynyl C 2-20 alkynyl
  • C 2-50 alkynyl alone or in combination means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon triple bond having 2 to 10, 2 to 20 or 2 to 50 carbon atoms, respectively.
  • Each hydrogen atom of a C 2-10 alkynyl, C 2-20 alkynyl or C 2-50 alkynyl group may optionally be replaced by a substituent as defined above.
  • one or more double bond(s) may occur.
  • a C 2-10 alkynyl, C 2-20 alkynyl or C 2-50 alkynyl may be interrupted by one or more moieties as defined below.
  • a C 1-4 alkyl, C 1-6 alkyl, C 1-10 alkyl, C 1-20 alkyl, C 1-50 alkyl, C 2-6 alkenyl, C 2-10 alkenyl, C 2-20 alkenyl, C 2-50 alkenyl, C 2-6 alkynyl, C 2-10 alkynyl, C 2-20 alkenyl or C 2-50 alkynyl may optionally be interrupted by one or more moieties which are preferably selected from the group consisting of
  • C 3-10 cycloalkyl means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.
  • Each hydrogen atom of a C 3-10 cycloalkyl carbon may be replaced by a substituent as defined above.
  • the term “C 3-10 cycloalkyl” also includes bridged bicycles like norbornane or norbornene.
  • 8- to 30-membered carbopolycyclyl or “8- to 30-membered carbopolycycle” means a cyclic moiety of two or more rings with 8 to 30 ring atoms, where two neighboring rings share at least one ring atom and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated).
  • a 8- to 30-membered carbopolycyclyl means a cyclic moiety of two, three, four or five rings, more preferably of two, three or four rings.
  • the term “3- to 10-membered heterocyclyl” or “3- to 10-membered heterocycle” means a ring with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including —S(O)—, —S(O) 2 —), oxygen and nitrogen (including ⁇ N(O)—) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom.
  • 3- to 10-membered heterocycles include but are not limited to aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetra
  • the term “8- to 11-membered heterobicyclyl” or “8- to 11-membered heterobicycle” means a heterocyclic moiety of two rings with 8 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including —S(O)—, —S(O) 2 —), oxygen and nitrogen (including ⁇ N(O)—) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom.
  • Examples for an 8- to 11-membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine and pteridine.
  • 8- to 11-membered heterobicycle also includes spiro structures of two rings like 1,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.
  • Each hydrogen atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicycle carbon may be replaced by a substituent as defined below.
  • the term “8- to 30-membered heteropolycyclyl” or “8- to 30-membered heteropolycycle” means a heterocyclic moiety of more than two rings with 8 to 30 ring atoms, preferably of three, four or five rings, where two neighboring rings share at least one ring atom and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or unsaturated), wherein at least one ring atom up to 10 ring atoms are replaced by a heteroatom selected from the group of sulfur (including —S(O)—, —S(O) 2 —), oxygen and nitrogen (including ⁇ N(O)—) and wherein the ring is linked to the rest of a molecule via a carbon or nitrogen atom.
  • R x and R y form the following structure:
  • R is C 3-10 cycloalkyl or 3- to 10-membered heterocyclyl.
  • R x and R y form the following structure:
  • halogen means fluoro, chloro, bromo or iodo. In certain embodiments halogen is fluoro or chloro.
  • the sustained-release PTH compound is for use in a method of improving the physical well-being of patients having hypoparathyroidism. In certain embodiments the sustained-release PTH compound is for use in a method of treating the physical well-being of patients having hypoparathyroidism. In certain embodiments the sustained-release PTH compound is for use in a method of improving the mental well-being of patients having hypoparathyroidism. In certain embodiments the sustained-release PTH compound for use in a method of treating the mental well-being of patients having hypoparathyroidism.
  • the patient is a mammalian patient, such as a human patient. In certain embodiments the patient is an adult. In certain embodiments the patient is an adolescent. In certain embodiments the patient is a child.
  • hypoparathyroidism originates from surgery. In certain embodiments the hypoparathyroidism originates from an autoimmune disease. In certain embodiments the hypoparathyroidism is a consequence of DiGeorge syndrome. In certain embodiments the hypoparathyroidism is idiopathic.
  • the sustained-release PTH compound is administered no more than every 12 hours. In certain embodiments the sustained-release PTH compound is administered every 12 hours. In certain embodiments the sustained-release PTH compound is administered no more than every 24 hours. In certain embodiments the sustained-release PTH compound is administered every 24 hours. In certain embodiments the sustained-release PTH compound is administered no more than every 36 hours. In certain embodiments the sustained-release PTH compound is administered every 36 hours. In certain embodiments the sustained-release PTH compound is administered no more than every 48 hours. In certain embodiments the sustained-release PTH compound is administered every 48 hours. In certain embodiments the sustained-release PTH compound is administered no more than every 72 hours. In certain embodiments the sustained-release PTH compound is administered every 72 hours.
  • the sustained-release PTH compound is administered no more than every 96 hours. In certain embodiments the sustained-release PTH compound is administered every 96 hours. In certain embodiments the sustained-release PTH compound is administered no more than every 120 hours. In certain embodiments the sustained-release PTH compound is administered every 120 hours. In certain embodiments the sustained-release PTH compound is administered no more than every 144 hours. In certain embodiments the sustained-release PTH compound is administered every 144 hours. In certain embodiments the sustained-release PTH compound is administered no more than every 168 hours. In certain embodiments the sustained-release PTH compound is administered every 168 hours. In certain embodiments the sustained-release PTH compound is administered no more than once every two weeks. In certain embodiments the sustained-release PTH compound is administered once every two weeks. In certain embodiments the sustained-release PTH compound is administered daily. In certain embodiments the sustained-release PTH compound is administered weekly.
  • Administration of the sustained-release PTH compound is in certain embodiments via subcutaneous administration. In certain embodiments administration of the sustained-release PTH compound is via intravenous administration. In certain embodiments administration of the sustained-release PTH compound is via intramuscular administration.
  • the sustained-release PTH compound releases PTH with a half-life of at least 12 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 24 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 36 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 48 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 60 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 72 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 84 hours.
  • the sustained-release PTH compound releases PTH with a half-life of at least 96 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 108 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 120 hours. In certain embodiments the sustained-release PTH compound releases PTH with a half-life of at least 144 hours.
  • the released PTH is a C-terminally truncated PTH, such as a C-terminally truncated PTH selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100,
  • the released PTH has a sequence selected from the group consisting of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 SEQ ID NO:115 and sequences having at least 90% homology thereto.
  • the released PTH is selected from the group consisting of SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112 and sequences having at least 90% homology thereto.
  • the released PTH has the sequence of SEQ ID NO:50. In certain embodiments the released PTH has the sequence of SEQ ID NO:52. In certain embodiments the released PTH has the sequence of SEQ ID NO:110. In certain embodiments the released PTH has the sequence of SEQ ID NO:111. In certain embodiments the released PTH has the sequence of SEQ ID NO:112. In certain embodiments the released PTH has the sequence of SEQ ID NO:51.
  • the sustained-release PTH compound is water-insoluble.
  • such water-insoluble sustained-release PTH compound is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres and microspheres.
  • the water-insoluble sustained-release PTH compound is a crystal comprising at least one PTH molecule or PTH moiety.
  • the water-insoluble sustained-release PTH compound is a nanoparticle comprising at least one PTH molecule or PTH moiety.
  • the water-insoluble sustained-release PTH compound is a microparticle comprising at least one PTH molecule or PTH moiety.
  • the water-insoluble sustained-release PTH compound is a nanosphere comprising at least one PTH molecule or PTH moiety.
  • the water-insoluble sustained-release PTH compound is a microsphere comprising at least one PTH molecule or PTH moiety. In certain embodiments the water-insoluble sustained-release PTH compound is a vesicle comprising at least one PTH molecule or PTH moiety, such as a micelle, liposome or polymersome. In certain embodiments the water-insoluble sustained-release PTH compound is a micelle comprising at least one PTH molecule or PTH moiety.
  • the water-insoluble sustained-release PTH compound is a liposome comprising at least one PTH molecule or PTH moiety, such as a liposome selected from the group consisting of aquasomes; non-ionic surfactant vesicles, such as niosomes and proniosomes; cationic liposomes, such as LeciPlex; transfersomes; ethosomes; ufasomes; sphingosomes; and pharmacosomes.
  • the water-insoluble sustained-release PTH compound is a polymersome comprising at least one PTH molecule or PTH moiety.
  • the water-insoluble sustained-release PTH compound comprises at least one PTH molecule non-covalently embedded in a water-insoluble polymer comprising for example a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoryl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxy
  • the water-insoluble sustained-release PTH compound comprises at least one PTH molecule non-covalently embedded in poly(lactic-co-glycolic acid) (PLGA).
  • PLGA poly(lactic-co-glycolic acid)
  • the water-insoluble sustained-release PTH compound comprises at least one PTH moiety covalently and reversibly conjugated to a water-insoluble polymer that may for example be selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly
  • the water-insoluble sustained-release PTH compound is a conjugate or its pharmaceutically acceptable salt comprising a carrier moiety Z′ to which one or more moieties -L 2 -L 1 -D are conjugated, wherein
  • Z′ is a hydrogel, such as a hydrogel comprising a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxymethacryl
  • Z′ is a poly(alkylene glycol)-based hydrogel, such as a poly(propylene glycol)-based hydrogel or a poly(ethylene glycol)-based (PEG-based) hydrogel, or a hyaluronic acid-based hydrogel.
  • Z′ is a PEG-based hydrogel.
  • PEG-based hydrogel may be degradable or may be non-degradable, i.e. stable.
  • PEG-based hydrogel is degradable.
  • PEG-based hydrogel is non-degradable.
  • Suitable hydrogels are known in the art. Examples are WO2006/003014, WO2011/012715 and WO2014/056926, which are herewith incorporated by reference.
  • Z′ is a hyaluronic acid-based hydrogel.
  • Z′ is a hydrogel as disclosed in WO2013/036847.
  • Z′ is a hydrogel produced by a method comprising the step of reacting at least a first reactive polymer with a cleavable crosslinker compound, wherein said cleavable crosslinker compound comprises a first functional group —Y 1 that reacts with the first reactive polymer and further comprises a moiety that is cleaved by elimination under physiological conditions wherein said moiety comprises a second functional group —Y 2 that reacts with a second reactive polymer.
  • the cleavable crosslinker compound is of formula (PL-1)
  • each —R 5 is independently selected from the group consisting of —H, alkyl, alkenylalkyl, alkynylalkyl, (OCH 2 CH 2 ) p O-alkyl with p being an integer ranging from 1 to 1000, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
  • —X of formula (PL-1) is selected from the group consisting of succinimidyl carbonate, sulfosuccinimidyl carbonate halides, thioethers, esters, nitrophenyl carbonate, chloroformate, fluoroformate, optionally substituted phenols and formula (PL-2)
  • —X of formula (PL-1) comprises an activated carbonate such as succinimidyl carbonate, sulfosuccinimidyl carbonate, or nitrophenyl carbonate.
  • —X of formula (PL-1) comprises a carbonyl halide such as O(C ⁇ O)Cl or O(C ⁇ O)F.
  • —X of formula (PL-1) has the formula (PL-2).
  • —X of formula (PL-1) is OR 7 or SR 7 , wherein R 7 is optionally substituted alkylene, optionally substituted phenylene or (OCH 2 CH 2 ) p , wherein p is 1 to 1000.
  • p of formula (PL-2) is an integer ranging from 1 to 100. In certain embodiments p of formula (PL-2) is an integer ranging from 1 to 10.
  • —Y 1 of formula (PL-1) and —Y 2 of formula (PL-2) independently comprise N 3 , NH 2 , NH—CO 2 t Bu, SH, S t Bu, maleimide, CO 2 H, CO 2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide, wherein tBu is tert-butyl, and wherein when one of Y 1 or Y 2 comprises N 3 the other does not comprise alkyne or cyclooctyne; when one of —Y 1 or —Y 2 comprises SH the other does not comprise maleimide, acrylate or acrylamide; when one of —Y 1 or —Y 2 comprises NH 2 the other does not comprise CO 2 H; when one of —Y 1 or Y 2 comprises 1,3-diene or cyclopentadiene the other does not comprise furan.
  • the cleavable linker compound is of formula (PL-3)
  • t of formula (PL-3) is 2. In certain embodiments t of formula (PL-3) is 4. In certain embodiments t of formula (PL-3) is 8. In certain embodiments t of formula (PL-3) is 16. In certain embodiments t of formula (PL-3) is 32.
  • —Q of formula (PL-3) has a structure selected from the group consisting of
  • —Q of formula (PL-3) has the structure of (PL-3-i). In certain embodiments —Q of formula (PL-3) has the structure of (PL-3-ii). In certain embodiments —Q of formula (PL-3) has the structure of (PL-3-iii).
  • the cleavable crosslinker compound is of formula (PL-3), wherein m is 0, n is approximately 100, s is 0, t is 4, —W— is —O(C ⁇ O)NH—, —Q has the structure of (PL-3-i), —R 2 is H, one —R 5 is —H and the other —R 5 is (CH 2 ) 5 N 3 , and —R 1 is (4-chlorophenyl)SO 2 , phenyl substituted with —SO 2 , morpholino-SO 2 , or —CN.
  • —Y 1 of formula (PL-3) comprises N 3 , NH 2 , NH—CO 2 t Bu, SH, S t Bu, maleimide, CO 2 H, CO 2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide, wherein tBu is tert-butyl.
  • Z1 of formula (PL-1) comprises N 3 , NH 2 , NH—CO 2 t Bu, SH, S t Bu, maleimide, CO 2 H, CO 2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide.
  • each —Y 1 and of formula (PL-1) or (PL-3) and —Y 2 of formula (PL-2) independently comprises N 3 , NH 2 , NH—CO 2 t Bu, SH, S t Bu, maleimide, CO 2 H, CO 2 t Bu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate or acrylamide.
  • one of —Y 1 and —Y 2 is azide and the other is a reactive functional group selected from the group consisting of acetylene, cyclooctyne, and maleimide.
  • one of —Y 1 and —Y 2 is thiol and the other is a reactive functional group selected from the group consisting of maleimide, acrylate, acrylamide, vinylsulfone, vinylsulfonamide, and halocarbonyl.
  • one of —Y 1 and —Y 2 is amine and the other is a selective reactive functional group selected from carboxylic acid and activated carboxylic acid.
  • one of —Y 1 and —Y 2 is maleimide and the other is a selective reactive functional group selected from the group consisting of 1,3-diene, cyclopentadiene, and furan.
  • the first and any second polymer is selected from the group consisting of homopolymeric or copolymeric polyethylene glycols, polypropylene glycols, poly(N-vinylpyrrolidone), polymethacrylates, polyphosphazenes, polylactides, polyacrylamides, polyglycolates, polyethylene imines, agaroses, dextrans, gelatins, collagens, polylysines, chitosans, alginates, hyaluronans, pectins and carrageenans that either comprise suitable reactive functionalities or is of formula [Y 3 —(CH 2 ) s (CH 2 CH 2 O) n ] t Q, wherein Y 3 is a reactive functional group, s is 0, 1 or 2, n is an integer selected from the group ranging from 10 to 1000, Q is a core group having valency t, and t is selected from the group consisting of 2, 4, 8, 16 or 32.
  • first and a second reactive polymer are reacted with said cleavable crosslinker compound, either sequentially or simultaneously.
  • first and second functional groups are the same.
  • the first polymer comprises a multi-arm polymer. In certain embodiments the first polymer comprises at least three arms. In certain embodiments the first polymer comprises at least four arms. In certain embodiments the first polymer comprises at least five arms. In certain embodiments the first polymer comprises at least six arms. In certain embodiments the first polymer comprises at least seven arms. In certain embodiments the first polymer comprises at least eight arms.
  • the second polymer comprises a multi-arm polymer. In certain embodiments the second polymer comprises at least three arms. In certain embodiments the second polymer comprises at least four arms. In certain embodiments the second polymer comprises at least five arms. In certain embodiments the second polymer comprises at least six arms. In certain embodiments the second polymer comprises at least seven arms. In certain embodiments the second polymer comprises at least eight arms.
  • the first polymer comprises a 2-arm polyethylene glycol polymer. In certain embodiments the first polymer comprises a 4-arm polyethylene glycol polymer. In certain embodiments the first polymer comprises an 8-arm polyethylene glycol polymer. In certain embodiments the first polymer comprises a 16-arm polyethylene glycol polymer. In certain embodiments the first polymer comprises a 32-arm polyethylene glycol polymer.
  • the second polymer comprises a 2-arm polyethylene glycol polymer. In certain embodiments the second polymer comprises a 4-arm polyethylene glycol polymer. In certain embodiments the second polymer comprises an 8-arm polyethylene glycol polymer. In certain embodiments the second polymer comprises a 16-arm polyethylene glycol polymer.
  • the second polymer comprises a 32-arm polyethylene glycol polymer.
  • first and a second reactive polymer are reacted with said cleavable crosslinker compound, either sequentially or simultaneously.
  • first and second functional groups are the same.
  • a moiety capable of being cleaved by elimination under physiological conditions refers to a structure comprising a group H—C—(CH ⁇ CH) m —C—X′ wherein m is 0 or 1 and X′ is a leaving group, wherein an elimination reaction as described above to remove the elements of HX′ can occur at a rate such that the half-life of the reaction is between 1 and 10,000 hours under physiological conditions of pH and temperature.
  • the half-life of the reaction is between 1 and 5,000 hours, and more preferably between 1 and 1,000 hours, under physiological conditions of pH and temperature.
  • physiological conditions of pH and temperature is meant a pH of between 7 and 8 and a temperature between 30 and 40 degrees centigrade
  • reactive polymer and reactive oligomer refers to a polymer or oligomer comprising functional groups that are reactive towards other functional groups, most preferably under mild conditions compatible with the stability requirements of peptides, proteins, and other biomolecules.
  • Suitable functional groups found in reactive polymers include maleimides, thiols or protected thiols, alcohols, acrylates, acrylamides, amines or protected amines, carboxylic acids or protected carboxylic acids, azides, alkynes including cycloalkynes, 1,3-dienes including cyclopentadienes and furans, alpha-halocarbonyls, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl esters or carbonates.
  • the term “functional group capable of connecting to a reactive polymer” refers to a functional group that reacts to a corresponding functional group of a reactive polymer to form a covalent bond to the polymer.
  • Suitable functional groups capable of connecting to a reactive polymer include maleimides, thiols or protected thiols, acrylates, acrylamides, amines or protected amines, carboxylic acids or protected carboxylic acids, azides, alkynes including cycloalkynes, 1,3-dienes including cyclopentadienes and furans, alpha-halocarbonyls, and N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, or nitrophenyl esters or carbonates.
  • substituted refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group comprising one or more substituent groups in place of one or more hydrogen atoms.
  • Substituent groups may generally be selected from halogen including F, Cl, Br, and I; lower alkyl including linear, branched, and cyclic; lower haloalkyl including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; OH; lower alkoxy including linear, branched, and cyclic; SH; lower alkylthio including linear, branched, and cyclic; amino, alkylamino, dialkylamino, silyl including alkylsilyl, alkoxysilyl, and arylsilyl; nitro; cyano; carbonyl; carboxylic acid, carboxylic ester, carboxylic amide; aminocarbonyl; aminoacyl; carbamate;
  • R 1 and R 2 may be modulated by the optional addition of electron-donating or electron-withdrawing substituents.
  • electron-donating group is meant a substituent resulting in a decrease in the acidity of the R 1 R 2 CH; electron-donating groups are typically associated with negative Hammett ⁇ or Taft ⁇ * constants and are well-known in the art of physical organic chemistry. (Hammett constants refer to aryl/heteroaryl substituents, Taft constants refer to substituents on non-aromatic moieties.)
  • suitable electron-donating substituents include lower alkyl, lower alkoxy, lower alkylthio, amino, alkylamino, dialkylamino, and silyl.
  • electron-withdrawing group refers to a substituent resulting in an increase in the acidity of the R 1 R 2 CH group; electron-withdrawing groups are typically associated with positive Hammett a or Taft a* constants and are well-known in the art of physical organic chemistry.
  • suitable electron-withdrawing substituents include halogen, difluoromethyl, trifluoromethyl, nitro, cyano, C( ⁇ O)—R x , wherein —R x is H, lower alkyl, lower alkoxy, or amino, or S(O) m R y , wherein m is 1 or 2 and —R y is lower alkyl, aryl, or heteroaryl.
  • an alkoxy substituent on the ortho- or para-position of an aryl ring is electron-donating, and is characterized by a negative Hammett a constant
  • an alkoxy substituent on the meta-position of an aryl ring is electron- withdrawing and is characterized by a positive Hammett a constant.
  • alkyl alkenyl
  • alkynyl include linear, branched or cyclic hydrocarbon groups of 1 to 8 carbons or 1 to 6 carbons or 1 to 4 carbons wherein alkyl is a saturated hydrocarbon, alkenyl includes one or more carbon-carbon double bonds and alkynyl includes one or more carbon-carbon triple bonds. Unless otherwise specified these contain 1 to 6 carbons.
  • aryl includes aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl.
  • Heteroaryl includes aromatic rings comprising 3 to 15 carbons containing at least one N, O or S atom, preferably 3 to 7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar.
  • halogen includes fluoro, chloro, bromo and iodo.
  • maleimido is a group of the formula
  • Z′ is a hydrogel as disclosed in WO2020/206358 A1.
  • Z′ is a hydrogel produced by a method comprising the steps of
  • —Z′ is a hydrogel obtainable from the method described above.
  • the hydrogel produced by the preceding method is degradable.
  • —Y and —Y′′ react under step (c) to form an insoluble hydrogel matrix comprising crosslinks of formula (PL-4′):
  • n of formula (PL-4) or (PL-4′) is an integer selected from 1, 2, 3, 4, 5 and 6. In certain embodiments n of formula (PL-4) or (PL-4′) is an integer selected from 1, 2 and 3. In certain embodiments n of formula (PL-4) or (PL-4′) is an integer selected from 0, 1, 2 and 3. In certain embodiments n of formula (PL-4) or (PL-4′) is 1. In certain embodiments n of formula (PL-4) is 2. In certain embodiments n of formula (PL-4) or (PL-4′) is 3.
  • the multi-arm —P 2 of formula (PL-4) or (PL-4′) is an r-armed polymer, wherein r is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. In certain embodiments r of formula (PL-4) or (PL-4′) is an integer selected from 2, 3, 4, 5, 6, 7 and 8. In certain embodiments r of formula (PL-4) or (PL-4′) is an integer selected from 2, 4, 6 and 8. In certain embodiments r of formula (PL-4) or (PL-4′) is 2. In certain embodiments r of formula (PL-4) or (PL-4′) is 4. In certain embodiments r of formula (PL-4) or (PL-4′) is 6. In certain embodiments r of formula (PL-4) or (PL-4′) is 8.
  • —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of at least 1 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of 1 to 100 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of 1 to 80 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of 1 to 60 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of 1 to 40 kDa.
  • —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of 1 to 20 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of 1 to 10 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of 1 to 5 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of about 20 kDa. In certain embodiments —P 2 of formula (PL-4) or (PL-4′) has a molecular weight of about 40 kDa.
  • the multi-arm polymer —P 1 of step (b) is an r-armed polymer, wherein r is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. In certain embodiments the multi-arm —P 1 of step (b) is an r-armed polymer, wherein r is an integer selected from 2, 3, 4, 5, 6, 7 and 8. In certain embodiments the multi-arm —P 1 of step (b) is an r-armed polymer, wherein r is an integer selected from 2, 4, 6 and 8. In certain embodiments the multi-arm —P 1 of step (b) is an r-armed polymer, wherein r is 2.
  • the multi-arm —P 1 of step (b) is an r-armed polymer, wherein r is 4. In certain embodiments the multi-arm —P 1 of step (b) is an r-armed polymer, wherein r is 6. In certain embodiments the multi-arm —P 1 of step (b) is an r-armed polymer, wherein r is 8.
  • —P 1 of step (b) has a molecular weight of at least 1 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of 1 to 100 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of 1 to 80 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of 1 to 60 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of 1 to 40 kDa.
  • the multi-arm polymer —P 1 of step (b) has a molecular weight of 1 to 20 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of 1 to 10 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of 1 to 5 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of about 20 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of about 40 kDa.
  • the multi-arm polymer —P 1 of step (b) has a molecular weight of about 60 kDa. In certain embodiments the multi-arm polymer —P 1 of step (b) has a molecular weight of about 80 kDa.
  • —P 1 of step (b) and —P 2 of formula (PL-4) or (PL-4′) comprise poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), poly(ethylene imine) (PEI), dextrans, hyaluronic acids, or co-polymers thereof.
  • —P 1 of step (b) and P 2 of formula (PL-4) or (PL-4′) are PEG-based polymers.
  • —P 1 of step (b) and —P 2 of formula (PL-4) or (PL-4′) are hyaluronic acid-based polymers.
  • —R 1 and —R 2 of formula (PL-4) or (PL-4′) are independently electron-withdrawing groups, alkyl, or —H, and wherein at least one of —R 1 and —R 2 is an electron-withdrawing group.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —CN, —NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, —COR 3 , —SOR 3 , or —SO 2 R 3 , wherein —R 3 is —H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR 8 or —NR 8 2 , wherein each —R 8 is independently —H or optionally substituted alkyl, or both —R 8 groups are taken together with the nitrogen to which they are attached to form a heterocyclic ring; or —SR 9 , wherein —R 9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted
  • the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —CN. In certain embodiments the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —NO 2 . In certain embodiments the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is optionally substituted aryl containing 6 to 10 carbons. In certain embodiments the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is optionally substituted phenyl, naphthyl, or anthracenyl.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is optionally substituted heteroaryl comprising 3 to 7 carbons and containing at least one N, O, or S atom.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is optionally substituted alkenyl containing 2 to 20 carbon atoms. In certain embodiments the electron- withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is optionally substituted alkynyl containing 2 to 20 carbon atoms.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —COR 3 , —SOR 3 , or —SO 2 R 3 , wherein R 3 is —H, optionally substituted alkyl containing 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR 8 or —NR 8 2 , wherein each —R 8 is independently —H or optionally substituted alkyl containing 1 to 20 carbon atoms, or both —R 8 groups are taken together with the nitrogen to which they are attached to form a heterocyclic ring.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —SR 9 , wherein —R 9 is optionally substituted alkyl containing 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl. In certain embodiments at least one of —R 1 and —R 2 is —CN or —SO 2 R 3 .
  • At least one of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —CN, —SOR 3 or —SO 2 R 3 . In certain embodiments at least one of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —CN or —SO 2 R 3 . In certain embodiments at least one of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —CN or —SO 2 R 3 , wherein —R 3 is optionally substituted alkyl, optionally substituted aryl, or —NR 8 2 .
  • At least one of —R 1 and —R 2 of formula (PL-4) or (PL-4′) is —CN, —SO 2 N(CH 3 ) 2 , —SO 2 CH 3 , phenyl substituted with —SO 2 , phenyl substituted with —SO 2 and —Cl, —SO 2 N(CH 2 CH 2 ) 20 , —SO 2 CH(CH 3 ) 2 , —SO 2 N(CH 3 )(CH 2 CH 3 ), or —SO 2 N(CH 2 CH 2 OCH 3 ) 2 .
  • each —R 4 of formula (PL-4) or (PL-4′) is independently C 1 -C 3 alkyl or taken together may form a 3- to 6-membered ring. In certain embodiments each —R 4 of formula (PL-4) or (PL-4′) is independently C 1 -C 3 alkyl. In certain embodiments both —R 4 of formula (PL-4) or (PL-4′) are methyl.
  • —Y and —Y′′ are independently selected from the group consisting of amine, aminooxy, ketone, aldehyde, maleimidyl, thiol, alcohol, azide, 1,2,4,6-tetrazinyl, trans-cyclooctenyl, bicyclononynyl, cyclooctynyl, and protected variants thereof.
  • Y and Y′′ may react with each other such as in a selective way.
  • —Y is amine
  • —Y′′ is carboxylic acid, active ester, or active carbonate to yield a residual connecting functional group —Y*— that is amide or carbamate.
  • —Y is azide
  • —Y′′ is alkynyl, bicyclononynyl, or cyclooctynyl to yield a residual connecting functional group —Y*— that is 1,2,3-triazole.
  • —Y is NH 2 O
  • —Y′′ is ketone or aldehyde to yield a residual connecting functional group —Y*— that is oxime.
  • —Y is SH
  • —Y′′ is maleimide or halocarbonyl to yield a residual connecting functional group —Y*— that is thiosuccinimidyl or thioether.
  • these roles of —Y and —Y′′ can be reversed to yield —Y*— of opposing orientation.
  • —Y*— comprises an amide, oxime, 1,2,3-triazole, thioether, thiosuccinimide, or ether. In certain embodiments —Y*— is -L 2 -.
  • conjugation reactions may be performed under conditions known in the art, for example when —Y is azide and —Y′′ is cyclooctyne the conjugation occurs in any solvent wherein both components show adequate solubility, although it is known that aqueous solutions show more favorable reaction rates.
  • an appropriate solvent typically an aqueous buffer at a pH of 2 to 7 when —Y and —Y′′ are azide/cyclooctyne, or at a pH of 6 to 9 when —Y and —Y′′ are an activated ester and an amine
  • the —Y and —Y′′ groups react to form an insoluble hydrogel matrix comprising crosslinks of formula (PL-4′).
  • This process may be carried out in bulk phase, or under conditions of emulsification in a mixed organic/aqueous system so as to form microparticle suspensions such as microspheres that are suitable for injection.
  • a conjugate comprising a hydrogel Z′ is produced by a method comprising the steps of
  • a conjugate is obtained by a method comprising the step of reacting a hydrogel Z′ with the linker-drug of formula (PL-5), wherein —B′ on the hydrogel Z′ reacts with —Y of formula (PL-5).
  • alkyl refers to linear, branched, or cyclic saturated hydrocarbon groups of 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • an alkyl is linear or branched.
  • linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, and n-decyl.
  • an alkyl is cyclic.
  • cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.
  • alkoxy refers to alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.
  • alkenyl refers to non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • alkynyl refers to non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • aryl refers to aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to aromatic rings comprising 3 to 15 carbons comprising at least one N, O or S atom, preferably 3 to 7 carbons comprising at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl.
  • alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkyl linkage.
  • the substituent will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl or heteroaryl is coupled.
  • halogen refers to bromo, fluoro, chloro and iodo.
  • heterocyclic ring or “heterocyclyl” refers to a 3- to 15-membered aromatic or non-aromatic ring comprising at least one N, O, or S atom.
  • examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term “heteroaryl” above.
  • a heterocyclic ring or heterocyclyl is non-aromatic.
  • a heterocyclic ring or heterocyclyl is aromatic.
  • substituents include alkyl, alkenyl, alkynyl, halogen, —CN, —OR aa , —SR aa , —NR aa R bb , —NO 2 , —C ⁇ NH(OR aa ), —C(O)R aa , —OC(O)R aa , —C(O)OR aa , —C(O)NR aa R bb , —OC(O)NR aa R bb , —NR aa C(O)R bb , —NR aa C(O)OR bb , —S(O)R aa , —S(O) 2 R aa ,
  • Z′ is a polymer network formed through the physical aggregation of polymer chains, which physical aggregation is in certain embodiments caused by hydrogen bonds, crystallization, helix formation or complexation.
  • such polymer network is a thermogelling polymer.
  • the sustained-release PTH compound is water-soluble.
  • such water-soluble sustained-release PTH compound is a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (Ia) and (Ib) are PTH prodrugs, more specifically water-soluble PTH prodrugs.
  • -D is a C-terminally truncated PTH, such as a C-terminally truncated PTH selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO
  • -D has a sequence selected from the group consisting of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 SEQ ID NO:115 and sequences having at least 90% homology thereto.
  • -D is selected from the group consisting of SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112 and sequences having at least 90% homology thereto.
  • -D has the sequence of SEQ ID NO:50. In certain embodiments -D has the sequence of SEQ ID NO:52. In certain embodiments -D has the sequence of SEQ ID NO:110. In certain embodiments -D has the sequence of SEQ ID NO:111. In certain embodiments -D has the sequence of SEQ ID NO:112. In certain embodiments -D has the sequence of SEQ ID NO:51.
  • the moiety -L 1 - is either conjugated to a functional group of the side chain of an amino acid residue of -D, to the N-terminal amine functional group or to the C-terminal carboxyl functional group of -D or to a nitrogen atom in the backbone polypeptide chain of -D.
  • Attachment to either the N-terminus or C-terminus can either be directly through the corresponding amine or carboxyl functional group, respectively, or indirectly wherein a spacer moiety is first conjugated to the amine or carboxyl functional group to which spacer moiety -L 1 - is conjugated.
  • the amino acid residue of PTH to which -L 1 - is conjugated comprises a functional group selected from the group consisting carboxylic acid, primary amine, secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, sulfate, disulfide, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, guanidine and aziridine.
  • a functional group selected from the group consisting carboxylic acid, primary amine, secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyan
  • the amino acid residue of PTH to which -L 1 - is conjugated comprises a functional group selected from the group consisting of hydroxyl, primary amine, secondary amine and guanidine. In certain embodiments the amino acid residue of PTH to which -L 1 - is conjugated comprises a primary or secondary amine functional group. In certain embodiments the amino acid residue of PTH to which -L 1 - is conjugated comprises a primary amine functional group.
  • the moiety -L 1 - is conjugated to a functional group of the side chain of an amino acid residue of PTH said amino acid residue is selected from the group consisting of proteinogenic amino acid residues and non-proteinogenic amino acid residues.
  • -L 1 - is conjugated to a functional group of the side chain of a proteinogenic amino acid residue of PTH.
  • -L 1 - is conjugated to a functional group of the side chain of a non-proteinogenic amino acid residue of PTH. It is understood that such non-proteinogenic amino acid is not found in the sequence of native PTH or fragments thereof and that it may only be present in variants and derivatives of PTH.
  • -L 1 - is conjugated to a functional group of the side chain of a proteinogenic amino acid residue of PTH.
  • said proteinogenic amino acid is selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine.
  • said proteinogenic amino acid is selected from the group consisting of lysine, aspartic acid, arginine and serine.
  • said proteinogenic amino acid is selected from the group consisting of lysine, arginine and serine.
  • -L 1 - is conjugated to a functional group of the side chain of a histidine of PTH.
  • -L 1 - is conjugated to a functional group of the side chain of a lysine of PTH. In certain embodiments -L 1 - is conjugated to a functional group of the side chain of a tryptophan of PTH. In certain embodiments -L 1 - is conjugated to a functional group of the side chain of a serine of PTH. In certain embodiments -L 1 - is conjugated to a functional group of the side chain of a threonine of PTH. In certain embodiments -L 1 - is conjugated to a functional group of the side chain of a tyrosine of PTH.
  • -L 1 - is conjugated to a functional group of the side chain of an aspartic acid of PTH. In certain embodiments -L 1 - is conjugated to a functional group of the side chain of a glutamic acid of PTH. In certain embodiments -L 1 - is conjugated to a functional group of the side chain of an arginine of PTH. It is understood that not every PTH moiety may comprise all of these amino acid residues.
  • -L 1 - is conjugated to the N-terminal amine functional group of PTH, either directly through the corresponding amine functional group or indirectly wherein a spacer moiety is first conjugated to the amine functional group to which spacer moiety -L 1 - is conjugated.
  • -L 1 - is directly conjugated to the N-terminal amine functional group of PTH.
  • -L 1 - is conjugated to the C-terminal functional group of PTH, either directly through the corresponding carboxyl functional group or indirectly wherein a spacer moiety is first conjugated to the carboxyl functional group to which spacer moiety -L 1 - is conjugated.
  • -L 1 - is directly conjugated to the N-terminal amine functional group of PTH.
  • the moiety -L 1 - can be connected to -D through any type of linkage, provided that it is reversible.
  • -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine.
  • -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate and acylguanidin. It is understood that some of these linkages are not reversible per se, but that in the present invention neighboring groups comprised in -L 1 - render these linkages reversible.
  • -L 1 - is connected to -D through an ester linkage. In certain embodiments -L 1 - is connected to -D through a carbamate linkage. In certain embodiments -L 1 - is connected to -D through an acylguanidine. In certain embodiments -L 1 - is connected to -D through an amide linkage.
  • the moiety -L 1 - is a reversible prodrug linker from which the drug, i.e. PTH, is released in its free form, i.e. it is a traceless prodrug linker.
  • Suitable prodrug linkers are known in the art, such as for example the reversible prodrug linker moieties disclosed in WO 2005/099768 A2, WO 2006/136586 A2, WO 2011/089216 A1 and WO 2013/024053 A1, which are incorporated by reference herewith.
  • -L 1 - is a reversible prodrug linker as described in WO 2011/012722 A1, WO 2011/089214 A1, WO 2011/089215 A1, WO 2013/024052 A1 and WO 2013/160340 A1 which are incorporated by reference herewith.
  • -L 1 - is disclosed in WO 2009/095479 A2. Accordingly, in certain embodiments the moiety -L 1 - is of formula (II):
  • R 7 is selected from the group consisting of —N(R 10 R 10a ); and —NR 10 —(C ⁇ O)—R 11 ;
  • -L 1 - of formula (II) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • Suitable 3- to 10-membered heterocycles formed by —R 3 /—R 3a of formula (II) together with the nitrogen atom to which they are attached are the following:
  • —R 1 or —R 1a of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 2 or —R 2a of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 3 or —R 3a of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 4 of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 5 or —R 5a of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 6 of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 7 or —R 7a of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 8 or —R 8a of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 9 or —R 9a of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 10 is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 11 is substituted with -L 2 -Z or -L 2 -Z′.
  • —R 3 of formula (II) is substituted with -L 2 -Z or -L 2 -Z′.
  • —X— of formula (II) is selected from the group consisting of —C(R 4 R 4a )—, —N(R 4 )— and —C(R 7 R 7a )—. In certain embodiments —X— of formula (II) is —C(R 4 R 4a )—.
  • —X— of formula (II) is —C(R 7 R 7a )—.
  • R 7 of formula (II) is —NR 10 —(C ⁇ O)—R 11 .
  • R 7a of formula (II) is selected from —H, methyl and ethyl. In certain embodiments —R 7a of formula (II) is —H.
  • R 10 is selected from —H, methyl and ethyl. In certain embodiments —R 10 is methyl.
  • —RH is selected from —H, methyl and ethyl. In certain embodiments —RH is —H. In certain embodiments —R 11 is substituted with -L 2 -Z or -L 2 -Z′.
  • —X— of formula (II) is —N(R 4 )—.
  • —R 4 is selected from the group consisting of —H, methyl and ethyl. In certain embodiments —R 4 is —H.
  • X 1 of formula (II) is C.
  • ⁇ X 3 of formula (II) is ⁇ O.
  • —X 2 — of formula (II) is —C(R 8 R 8a )—.
  • —R 8 and —R 8a of formula (II) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 8 and —R 8a of formula (II) is —H. In certain embodiments both —R 8 and —R 8a of formula (II) are —H.
  • —R 1 and —R 1a of formula (II) are independently selected from the group consisting of —H, methyl and ethyl.
  • At least one of —R 1 and —R 1a of formula (II) is —H. In certain embodiments —R 1 and —R 1a of formula (II) are —H.
  • At least one of —R 1 and —R 1a of formula (II) is methyl. In certain embodiments both —R 1 and —R 1a of formula (II) are methyl.
  • —R 2 and —R 2a of formula (II) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 2 and —R 2a of formula (II) is —H. In certain embodiments both —R 2 and —R 2a of formula (II) are H.
  • —R 3 and —R 3a of formula (II) are independently selected from the group consisting of —H, methyl, ethyl, propyl and butyl.
  • At least one of —R 3 and —R 3a of formula (II) is methyl. In certain embodiments —R 3 of formula (II) is methyl and —R 3a of formula (II) is —H.
  • —R 3 and —R 3a of formula (II) are both —H.
  • -D is connected to -L 1 - through a nitrogen by forming an amide bond.
  • the moiety -L 1 - is of formula (IIa-i):
  • -L 1 - of formula (IIa-i) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • the moiety -L 1 - of formula (IIa-i) is not further substituted.
  • —R 1 and —R 1a of formula (IIa-i) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 1 and —R 1a of formula (IIa-i) is —H. In certain embodiments both —R 1 and —R 1a of formula (IIa-i) are —H.
  • R 7 of formula (IIa-i) is —NR 10 —(C ⁇ O)—R 11 .
  • R 7a of formula (II-i) is selected from —H, methyl and ethyl. In certain embodiments —R 7a of formula (II-i) is —H.
  • R 10 of formula (IIa-i) is selected from —H, methyl and ethyl. In certain embodiments —R 10 of formula (IIa-i) is methyl.
  • R 11 of formula (IIa-i) is selected from —H, methyl and ethyl. In certain embodiments —R 11 of formula (IIa-i) is —H.
  • R 11 of formula (IIa-i) is substituted with -L 2 -Z or -L 2 -Z′.
  • —X 2 — of formula (IIa-i) is —C(R 8 R 8a )—.
  • —R 8 and —R 8a of formula (IIa-i) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 8 and —R 8a of formula (IIa-i) is —H. In certain embodiments both —R 8 and —R 8a of formula (IIa-i) are —H.
  • R 2 and —R 2a of formula (IIa-i) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 2 and —R 2a of formula (IIa-i) is —H. In certain embodiments both —R 2 and —R 2a of formula (IIa-i) are H.
  • —R 3 and —R 3a of formula (IIa-i) are independently selected from the group consisting of —H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of —R 3 and —R 3a of formula (IIa-i) is methyl.
  • —R 3 of formula (IIa-i) is —H and —R 3a of formula (IIa-i) is methyl.
  • the moiety -L 1 - is of formula (IIa-ii):
  • -L 1 - of formula (IIa-ii) is substituted with one moiety -L 2 -Z or -L 2 -Z′. In certain embodiments the moiety -L 1 - of formula (IIa-ii) is not further substituted.
  • —X 2 — of formula (IIa-ii) is —C(R 8 R 8a )—.
  • —R 8 and —R 8a of formula (IIa-ii) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 8 and —R 8a of formula (IIa-ii) is —H. In certain embodiments both —R 8 and —R 8a of formula (IIa-ii) are —H.
  • —R 3 and —R 3a of formula (IIa-ii) are independently selected from the group consisting of —H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of —R 3 and —R 3a of formula (IIa-ii) is methyl.
  • —R 3 of formula (IIa-ii) is —H and —R 3a of formula (IIa-ii) is methyl.
  • R 10 of formula (IIa-ii) is selected from —H, methyl and ethyl. In certain embodiments —R 11 of formula (IIa-ii) is methyl.
  • R 11 of formula (IIa-ii) is selected from —H, methyl and ethyl. In certain embodiments —R 11 of formula (IIa-ii) is —H.
  • RH of formula (IIa-ii) is substituted with -L 2 -Z or -L 2 -Z′.
  • the moiety -L 1 - is of formula (IIa-ii′):
  • the moiety -L 1 - of formula (IIa-ii′) is not further substituted.
  • —X 2 — of formula (IIa-ii′) is —C(R 8 R 8a )—.
  • —R 8 and —R 8a of formula (IIa-ii′) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 8 and —R 8a of formula (IIa-ii′) is —H. In certain embodiments both —R 8 and —R 8a of formula (IIa-ii′) are —H.
  • —R 3 and —R 3a of formula (IIa-ii′) are independently selected from the group consisting of —H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of —R 3 and —R 3a of formula (IIa-ii′) is methyl.
  • —R 3 of formula (IIa-ii′) is —H and —R 3a of formula (IIa-ii′) is methyl.
  • R 10 of formula (IIa-ii′) is selected from —H, methyl and ethyl. In certain embodiments —R 10 of formula (IIa-ii′) is methyl.
  • the moiety -L 1 - is of formula (IIa-iii):
  • -L 1 - of formula (IIa-iii) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • the moiety -L 1 - of formula (IIa-iii) is not further substituted.
  • the moiety -L 1 - is of formula (IIa-iii′):
  • the moiety -L 1 - of formula (IIa-iii′) is not further substituted.
  • the moiety -L 1 - is of formula (IIb-i)
  • -L 1 - of formula (IIb-i) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • the moiety -L 1 - of formula (IIb-i) is not further substituted.
  • —R 1 and —R 1a of formula (IIb-i) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 1 and —R 1a of formula (IIb-i) is methyl. In certain embodiments both —R 1 and —R 1a of formula (IIb-i) are methyl.
  • R 4 of formula (IIb-i) is selected from the group consisting of —H, methyl and ethyl. In certain embodiments —R 4 of formula (IIb-i) is —H.
  • —X 2 — of formula (IIb-i) is —C(R 8 R 8a )—.
  • —R 8 and —R 8a of formula (IIb-i) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 8 and —R 8a of formula (IIb-i) is —H. In certain embodiments both —R 8 and —R 8a of formula (IIb-i) are —H.
  • —R 2 and —R 2a of formula (IIb-i) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 2 and —R 2a of formula (IIb-i) is —H. In certain embodiments both —R 2 and —R 2a of formula (IIb-i) are H.
  • —R 3 and —R 3a of formula (IIb-i) are independently selected from the group consisting of —H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of —R 3 and —R 3a of formula (IIb-i) is —H. In certain embodiments both —R 3 and —R 3a of formula (IIb-i) are —H.
  • the moiety -L 1 - is of formula (IIb-ii):
  • -L 1 - of formula (IIb-ii) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • the moiety -L 1 - of formula (IIb-ii) is not further substituted.
  • —X 2 — of formula (IIb-ii) is —C(R 8 R 8a )—.
  • —R 8 and —R 8a of formula (IIb-ii) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 8 and —R 8a of formula (IIb-ii) is —H. In certain embodiments both —R 8 and —R 8a of formula (IIb-ii) are —H.
  • —R 2 and —R 2a of formula (IIb-ii) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 2 and —R 2a of formula (IIb-ii) is —H. In certain embodiments both —R 2 and —R 2a of formula (IIb-ii) are H.
  • —R 3 and —R 3a of formula (IIb-ii) are independently selected from the group consisting of —H, methyl, ethyl, propyl and butyl. In certain embodiments at least one of —R 3 and —R 3a of formula (IIb-ii) is —H. In certain embodiments both —R 3 and —R 3a of formula (IIb-ii) are —H.
  • the moiety -L 1 - is of formula (IIb-ii′):
  • the moiety -L 1 - of formula (IIb-ii′) is not further substituted.
  • —X 2 — of formula (IIb-ii′) is —C(R 8 R 8a )—.
  • —R 8 and —R 8a of formula (IIb-ii′) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 8 and —R 8a of formula (IIb-ii′) is —H. In certain embodiments both —R 8 and —R 8a of formula (IIb-ii′) are —H.
  • —R 2 and —R 2a of formula (IIb-ii′) are independently selected from the group consisting of —H, methyl and ethyl. In certain embodiments at least one of —R 2 and —R 2a of formula (IIb-ii′) is —H. In certain embodiments both —R 2 and —R 2a of formula (IIb-ii′) are H.
  • R 3a of formula (IIb-ii′) is selected from the group consisting of —H, methyl, ethyl, propyl and butyl. In one embodiment —R 3a of formula (IIb-ii′) is —H.
  • the moiety -L 1 - is of formula (IIb-iii):
  • -L 1 - of formula (IIb-iii) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • the moiety -L 1 - of formula (IIb-iii) is not further substituted.
  • the moiety -L 1 - is of formula (IIb-iii′):
  • the moiety -L 1 - of formula (IIb-iii′) is not further substituted.
  • -L 1 - is disclosed in WO2016/020373A1. Accordingly, in certain embodiments the moiety -L 1 - is of formula (III):
  • -L 1 - of formula (III) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • -L 1 - is as disclosed in EP1536334B1, WO2009/009712A1, WO2008/034122A1, WO2009/143412A2, WO2011/082368A2, and U.S. Pat. No. 8,618,124B2, which are herewith incorporated by reference in their entirety.
  • -L 1 - is as disclosed in U.S. Pat. No. 8,946,405B2 and U.S. Pat. No. 8,754,190B2, which are herewith incorporated by reference in their entirety. Accordingly, in certain embodiments -L 1 - is of formula (IV):
  • alkyl as used herein includes linear, branched or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or in some embodiments 1 to 6 or 1 to 4 carbon atoms.
  • alkoxy includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar.
  • alkenyl includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.
  • alkynyl includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.
  • aryl includes aromatic hydrocarbon groups of 6 to 18 carbons, such as 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl.
  • heteroaryl includes aromatic rings comprising 3 to 15 carbons containing at least one N, O or S atom, such as 3 to 7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar.
  • alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkylene linkage.
  • the substituent will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl or heteroaryl is coupled.
  • halogen includes bromo, fluoro, chloro and iodo.
  • heterocyclic ring refers to a 4 to 8 membered aromatic or non-aromatic ring comprising 3 to 7 carbon atoms and at least one N, O, or S atom.
  • Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term “heteroaryl” above.
  • suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or an additional ring, each optionally further substituted.
  • Optional substituents on any group, including the above, include halo, nitro, cyano, —OR, —SR, —NR 2 , —OCOR, —NRCOR, —COOR, —CONR 2 , —SOR, —SO 2 R, —SONR 2 , —SO 2 N R 2 , wherein each R is independently alkyl, alkenyl, alkynyl, aryl or heteroaryl, or two R groups taken together with the atoms to which they are attached form a ring.
  • -L 1 - of formula (IV) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • -L 1 - is as disclosed in WO2013/036857A1, which is herewith incorporated by reference in its entirety. Accordingly, in certain embodiments -L 1 - is of formula (V):
  • Alkyl “alkenyl”, and “alkynyl” include linear, branched or cyclic hydrocarbon groups of 1-8 carbons or 1-6 carbons or 1-4 carbons wherein alkyl is a saturated hydrocarbon, alkenyl includes one or more carbon-carbon double bonds and alkynyl includes one or more carbon-carbon triple bonds. Unless otherwise specified these contain 1-6 C.
  • Aryl includes aromatic hydrocarbon groups of 6-18 carbons, such as 6-10 carbons, including groups such as phenyl, naphthyl, and anthracene
  • Heteroaryl includes aromatic rings comprising 3-15 carbons containing at least one N, O or S atom, such as 3-7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiszolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar.
  • substituted means an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group comprising one or more substituent groups in place of one or more hydrogen atoms.
  • Substituents may generally be selected from halogen including F, Cl, Br, and I; lower alkyl including linear, branched, and cyclic; lower haloalkyl including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; OH; lower alkoxy including linear, branched, and cyclic; SH; lower alkylthio including linear, branched and cyclic; amino, alkylamino, dialkylamino, silyl including alkylsilyl, alkoxysilyl, and arylsilyl; nitro; cyano; carbonyl; carboxylic acid, carboxylic ester, carboxylic amide, aminocarbonyl; aminoacyl; carbamate; urea;
  • -L 1 - of formula (V) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • -L 1 - is as disclosed in U.S. Pat. No. 7,585,837B2, which is herewith incorporated by reference in its entirety. Accordingly, in certain embodiments -L 1 - is of formula (VI):
  • Suitable substituents for formulas (VI) are alkyl (such as C 1-6 alkyl), alkenyl (such as C 2-6 alkenyl), alkynyl (such as C 2-6 alkynyl), aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (such as aromatic 4 to 7 membered heterocycle) or halogen moieties.
  • alkyl alkoxy, alkoxyalkyl, aryl, “alkaryl” and “aralkyl” mean alkyl radicals of 1-8, such as 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and butyl, and aryl radicals of 6-10 carbon atoms, e.g. phenyl and naphthyl.
  • halogen includes bromo, fluoro, chloro and iodo.
  • -L 1 - of formula (VI) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • alkyl shall be understood to include, e.g. straight, branched, substituted C 1-12 alkyls, including alkoxy, C 3-8 cycloalkyls or substituted cycloalkyls, etc.
  • substituted shall be understood to include adding or replacing one or more atoms contained within a functional group or compounds with one or more different atoms.
  • Substituted alkyls include carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls and mercaptoalkyls; substituted cycloalkyls include moieties such as 4-chlorocyclohexyl; aryls include moieties such as napthyl; substituted aryls include moieties such as 3-bromo-phenyl; aralkyls include moieties such as toluyl; heteroalkyls include moieties such as ethylthiophene; substituted heteroalkyls include moieties such as 3-methoxythiophone; alkoxy includes moieities such as methoxy; and phenoxy includes moieties such as 3-nitrophenoxy.
  • Halo- shall be understood to include fluoro, chloro, iodo and bromo.
  • -L 1 - of formula (VII) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • -L 1 - comprises a substructure of formula (VIII)
  • -L 1 - of formula (VIII) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • -L 1 - comprises a substructure of formula (IX)
  • -L 1 - of formula (IX) is substituted with one moiety -L 2 -Z or -L 2 -Z′.
  • -L 1 - has a structure as disclosed in WO2020/206358 A1. Accordingly, in certain embodiments the moiety -L 1 - is of formula (X):
  • n of formula (X) is an integer selected from 1, 2, 3, 4, 5 and 6. In certain embodiments n of formula (X) is an integer selected from 1, 2 and 3. In certain embodiments n of formula (X) is an integer from 0, 1, 2 and 3. In certain embodiments n of formula (X) is 1. In certain embodiments n of formula (X) is 2. In certain embodiments n of formula (X) is 3.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (X) is selected from the group consisting of —CN; —NO 2 ; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; —COR 3 , —SOR 3 , or —SO 2 R 3 , wherein —R 3 is —H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR 8 or —NR 8 2 , wherein each —R 8 is independently —H or optionally substituted alkyl, or both —R 8 groups are taken together with the nitrogen to which they are attached to form a heterocyclic ring; or —SR 9 , wherein —R 9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted
  • the electron-withdrawing group of —R 1 and —R 2 of formula (X) is —CN. In certain embodiments the electron-withdrawing group of —R 1 and —R 2 of formula (X) is —NO 2 . In certain embodiments the electron-withdrawing group of —R 1 and —R 2 of formula (X) is optionally substituted aryl comprising 6 to 10 carbons. In certain embodiments the electron-withdrawing group of —R 1 and —R 2 of formula (X) is optionally substituted phenyl, naphthyl, or anthracenyl.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (X) is optionally substituted heteroaryl comprising 3 to 7 carbons and comprising at least one N, O, or S atom.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (X) is optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (X) is optionally substituted alkenyl containing 2 to 20 carbon atoms. In certain embodiments the electron-withdrawing group of —R 1 and —R 2 of formula (X) is optionally substituted alkynyl comprising 2 to 20 carbon atoms.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (X) is —COR 3 , —SOR 3 , or —SO 2 R 3 , wherein —R 3 is —H, optionally substituted alkyl comprising 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR 8 or —NR 8 2 , wherein each —R 8 is independently —H or optionally substituted alkyl comprising 1 to 20 carbon atoms, or both —R 8 groups are taken together with the nitrogen to which they are attached to form a heterocyclic ring.
  • the electron-withdrawing group of —R 1 and —R 2 of formula (X) is —SR 9 , wherein —R 9 is optionally substituted alkyl comprising 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl.
  • At least one of —R 1 or —R 2 of formula (X) is —CN, —SOR 3 or —SO 2 R 3 . In certain embodiments at least one of —R 1 and —R 2 of formula (X) is —CN or —SO 2 R 3 . In certain embodiments at least one of —R 1 and —R 2 of formula (X) is —CN or —SO 2 R 3 , wherein —R 3 is optionally substituted alkyl, optionally substituted aryl, or —NR 8 2 .
  • At least one of —R 1 and —R 2 of formula (X) is —CN, —SO 2 N(CH 3 ) 2 , —SO 2 CH 3 , phenyl substituted with —SO 2 , phenyl substituted with —SO 2 and —Cl, —SO 2 N(CH 2 CH 2 ) 2 O, —SO 2 CH(CH 3 ) 2 , —SO 2 N(CH 3 )(CH 2 CH 3 ), or —SO 2 N(CH 2 CH 2 OCH 3 ) 2 .
  • each —R 4 of formula (X) is independently C 1 -C 3 alkyl. In certain embodiments both —R 4 are methyl.
  • —Y— of formula (X) is absent. In certain embodiments —Y— of formula (X) is —N(R 6 )CH 2 —.
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is —CN, —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is —SO 2 N(CH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is SO 2 CH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is —SO 2 N(CH 2 CH 2 ) 2 CHCH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is phenyl substituted with —SO 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is phenyl substituted with —SO 2 and —Cl, —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is —SO 2 N(CH 2 CH 2 ) 20 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is —SO 2 CH(CH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is —SO 2 N(CH 3 )(CH 2 CH 3 ), —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is —SO 2 N(CH 2 CH 2 OCH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 1, —R 1 is phenyl substituted with —SO 2 and —CH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is —CN, —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is —SO 2 N(CH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is SO 2 CH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is —SO 2 N(CH 2 CH 2 ) 2 CHCH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is phenyl substituted with —SO 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is phenyl substituted with —SO 2 and —Cl, —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is —SO 2 N(CH 2 CH 2 ) 20 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is —SO 2 CH(CH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is —SO 2 N(CH 3 )(CH 2 CH 3 ), —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is —SO 2 N(CH 2 CH 2 OCH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 2, —R 1 is phenyl substituted with —SO 2 and —CH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is —CN, —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is —SO 2 N(CH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is SO 2 CH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is —SO 2 N(CH 2 CH 2 ) 2 CHCH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is phenyl substituted with —SO 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is phenyl substituted with —SO 2 and —Cl, —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is —SO 2 N(CH 2 CH 2 ) 20 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is —SO 2 CH(CH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is —SO 2 N(CH 3 )(CH 2 CH 3 ), —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is —SO 2 N(CH 2 CH 2 OCH 3 ) 2 , —R 2 is —H, and —R 4 is —CH 3 .
  • -L 1 - is of formula (X), wherein n is 3, —R 1 is phenyl substituted with —SO 2 and —CH 3 , —R 2 is —H, and —R 4 is —CH 3 .
  • alkyl refers to linear, branched, or cyclic saturated hydrocarbon groups of 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • an alkyl is linear or branched.
  • linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, and n-decyl.
  • an alkyl is cyclic.
  • cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.
  • alkoxy refers to alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.
  • alkenyl refers to non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • alkynyl refers to non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • aryl refers to aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to aromatic rings comprising 3 to 15 carbons comprising at least one N, O or S atom, preferably 3 to 7 carbons comprising at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl.
  • alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkyl linkage.
  • the substituent will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl or heteroaryl is coupled.
  • halogen refers to bromo, fluoro, chloro and iodo.
  • heterocyclic ring or “heterocyclyl” refers to a 3- to 15-membered aromatic or non-aromatic ring comprising at least one N, O, or S atom.
  • examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term “heteroaryl” above.
  • a heterocyclic ring or heterocyclyl is non-aromatic.
  • a heterocyclic ring or heterocyclyl is aromatic.
  • substituents include alkyl, alkenyl, alkynyl, halogen, —CN, —SR aa , —NR aa R bb , —NO 2 , —C ⁇ NH(OR aa ), —C(O)R′, —OC(O)R aa , —C(O)OR aa , —C(O)NR′R bb , —OC(O)NR aa R bb , —NR′C(O)R bb , —NR aa C(O)OR bb , —S(O)R aa , —S(O) 2 R aa , —NR aa S(O)R bb , —S(O)R aa , —S(O) 2 R aa , —NR aa S(O)R bb , —S(O)R aa , —
  • -L 2 - is a chemical bond.
  • -L 2 - is a spacer moiety, such as a spacer moiety selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—, —N(R y1 )S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 )—, C 1-50 alkyl, C
  • each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more —R y2 , which are the same or different;
  • -L 2 - is selected from -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—, —N(R y1 )S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 )—, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T-, C 1-20 alkyl, C 2-20 alken
  • -L 2 - is selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—, —N(R y1 )S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 )—, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T-, C 1-50 alkyl,
  • -L 2 - is selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—, —N(R y1 )S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 )—, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T-, C 1-50 alkyl,
  • -L 2 - is a C 1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from —O—, -T- and —C(O)N(R y1 )—; and which C 1-20 alkyl chain is optionally substituted with one or more groups independently selected from —OH, -T and —C(O)N(R y6 R y6a ); wherein —R y1 , —R y6 , —R y6a are independently selected from the group consisting of H and C 1-4 alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycycl
  • -L 2 - has a molecular weight in the range of from 14 g/mol to 750 g/mol.
  • -L 2 - comprises a moiety selected from
  • -L 2 - has a chain length of 1 to 20 atoms.
  • chain length refers to the number of atoms of -L 2 - present in the shortest connection between -L 1 - and —Z.
  • n of formula (i) is selected from the group consisting of 3, 4, 5, 6, 7, 8, and 9. In certain embodiments n of formula (i) is 4, 5, 6, or 7. In certain embodiments n of formula (i) is 4. In certain embodiments n of formula (i) is 5. In certain embodiments n of formula (i) is 6.
  • the moiety -L 1 -L 2 - is selected from the group consisting of
  • the moiety -L 1 -L 2 - is selected from the group consisting of
  • the moiety -L 1 -L 2 - is of formula (IIca-ii). In certain embodiments the moiety -L 1 -L 2 - is of formula (IIcb-iii).
  • the carrier —Z comprises a C 8-24 alkyl or a polymer.
  • —Z comprises a polymer, such as a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-o
  • —Z has a molecular weight ranging from 5 to 200 kDa. In certain embodiments —Z has a molecular weight ranging from 8 to 100 kDa, such as ranging from 10 to 80 kDa, from 12 to 60, or from 15 to 40. In certain embodiments —Z has a molecular weight of about 20 kDa. In certain embodiments —Z has a molecular weight of about 40 kDa.
  • —Z comprises a protein, such as a protein selected from the group consisting of carboxyl-terminal polypeptide of the chorionic gonadotropin as described in US 2012/0035101 A1 which are herewith incorporated by reference; albumin; XTEN sequences as described in WO 2011123813 A2 which are herewith incorporated by reference; proline/alanine random coil sequences as described in WO 2011/144756 A1 which are herewith incorporated by reference; proline/alanine/serine random coil sequences as described in WO 2008/155134 A1 and WO 2013/024049 A1 which are herewith incorporated by reference; and Fc fusion proteins.
  • —Z is a polysarcosine.
  • —Z comprises a poly(N-methylglycine). In certain embodiments —Z comprises a random coil protein moiety. In certain embodiments —Z comprises one random coil protein moiety. In certain embodiments —Z comprises two random coil proteins moieties. In certain embodiments —Z comprises three random coil proteins moieties. In certain embodiments —Z comprises four random coil proteins moieties. In certain embodiments —Z comprises five random coil proteins moieties. In certain embodiments —Z comprises six random coil proteins moieties. In certain embodiments —Z comprises seven random coil proteins moieties. In certain embodiments —Z comprises eight random coil proteins moieties.
  • such random coil protein moiety comprises at least 25 amino acid residues and at most 2000 amino acids. In certain embodiments such random coil protein moiety comprises at least 30 amino acid residues and at most 1500 amino acid residues. In certain embodiments such random coil protein moiety comprises at least 50 amino acid residues and at most 500 amino acid residues.
  • —Z comprises a random coil protein moiety of which at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as at least 98% or such as at least 99% of the total number of amino acids forming said random coil protein moiety are selected from alanine and proline. In certain embodiments at least 10%, but less than 75%, such as less than 65%, of the total number of amino acid residues of such random coil protein moiety are proline residues. In certain embodiments such random coil protein moiety is as described in WO 2011/144756 A1 which is hereby incorporated by reference in its entirety.
  • —Z comprises at least one moiety selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:51 and SEQ ID NO:61 as disclosed in WO2011/144756 which are hereby incorporated by reference.
  • a moiety comprising such random coil protein comprising alanine and proline will be referred to as “PA” or “PA moiety”.
  • —Z comprises a PA moiety.
  • —Z comprises a random coil protein moiety of which at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as at least 98% or such as at least 99% of the total number of amino acids forming said random coil protein moiety are selected from alanine, serine and proline. In certain embodiments at least 4%, but less than 40% of the total number of amino acid residues of such random coil protein moiety are proline residues. In certain embodiments such random coil protein moiety is as described in WO 2008/155134 A1 which is hereby incorporated by reference in its entirety.
  • —Z comprises at least one moiety selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54 and SEQ ID NO:56 as disclosed in WO 2008/155134 A1, which are hereby incorporated by reference.
  • a moiety comprising such random coil protein moiety comprising alanine, serine and proline will be referred to as “PAS” or “PAS mo
  • —Z comprises a PAS moiety.
  • —Z comprises a random coil protein moiety of which at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as at least 98% or such as at least 99% of the total number of amino acids forming said random coil protein moiety are selected from alanine, glycine, serine, threonine, glutamate and proline.
  • random coil protein moiety is as described in WO 2010/091122 A1 which is hereby incorporated by reference.
  • —Z comprises at least one moiety selected from the group consisting of SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184; SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:210
  • a moiety comprising such random coil protein moiety comprising alanine, glycine, serine, threonine, glutamate and proline will be referred to as “XTEN” or “XTEN moiety” in line with its designation in WO 2010/091122 A1.
  • —Z comprises an XTEN moiety.
  • —Z comprises a fatty acid derivate, such as a derivative as disclosed in WO 2005/027978 A2 and WO 2014/060512 A1 which are herewith incorporated by reference.
  • —Z is a hyaluronic acid-based polymer.
  • —Z is a carrier as disclosed in WO 2012/02047 A1 which is herewith incorporated by reference.
  • —Z is a carrier as disclosed in WO 2013/024048 A1 which is herewith incorporated by reference.
  • —Z is a PEG-based polymer, such as a linear, branched or multi-arm PEG-based polymer.
  • —Z is a linear PEG-based polymer.
  • —Z is a multi-arm PEG-based polymer. In certain embodiments —Z is a multi-arm PEG-based polymer having at least 4 PEG-based arms.
  • such multi-arm PEG-based polymer —Z is connected to a multitude of moieties -L 2 -L 1 -D, wherein each moiety -L 2 -L 1 -D is in certain embodiments connected to the end of an arm.
  • such multi-arm PEG-based polymer —Z is connected to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 moieties -L 2 -L 1 -D.
  • such multi-arm PEG-based polymer —Z is connected to 2, 3, 4, 6 or 8 moieties -L 2 -L 1 -D.
  • such multi-arm PEG-based polymer —Z is connected to 2, 4 or 6 moieties -L 2 -L 1 -D. In certain embodiments such multi-arm PEG-based polymer —Z is connected to 4 or 6 moieties -L 2 -L 1 -D. In certain embodiments such multi-arm PEG-based polymer —Z is connected to 4 moieties -L 2 -L 1 -D.
  • such multi-arm PEG-based polymer —Z is a multi-arm PEG derivative as, for instance, detailed in the products list of JenKem Technology, USA (accessed by download from http://www.jenkemusa.com/Pages/PEGProducts.aspx on Dec. 18, 2014), such as a 4-arm-PEG derivative, in particular a 4-arm-PEG comprising a pentaerythritol core, an 8-arm-PEG derivative comprising a hexaglycerin core, and an 8-arm-PEG derivative comprising a tripentaerythritol core.
  • the water-soluble PEG-based carrier —Z comprises a moiety selected from:
  • —Z is a branched PEG-based polymer. In certain embodiments —Z is a branched PEG-based polymer having one, two, three, four, five or six branching points. In certain embodiments —Z is a branched PEG-based polymer having one, two or three branching points. In certain embodiments —Z is a branched PEG-based polymer having one branching point. In certain embodiments —Z is a branched PEG-based polymer having two branching points. In certain embodiments —Z is a branched PEG-based polymer having three branching points.
  • a branching point may be selected from the group consisting of —N ⁇ , —CH ⁇ and >C ⁇ .
  • such branched PEG-based moiety —Z has a molecular weight of at least 10 kDa.
  • such branched moiety —Z has a molecular weight ranging from and including 10 kDa to 500 kDa, such as from and including 10 kDa to 250 Da, such as from and including 10 kDa to 150 kDa, such as from and including 12 kDa to 100 kDa or such as from and including 15 kDa to 80 kDa.
  • such branched moiety —Z has a molecular weight ranging from and including 10 kDa to 80 kDa. In certain embodiments the molecular weight is about 10 kDa. In certain embodiments the molecular weight of such branched moiety —Z is about 20 kDa. In certain embodiments the molecular weight of such branched moiety —Z is about 30 kDa. In certain embodiments the molecular weight of such branched moiety —Z is about 40 kDa. In certain embodiments the molecular weight of such branched moiety —Z is about 50 kDa. In certain embodiments the molecular weight of such branched moiety —Z is about 60 kDa.
  • the molecular weight of such branched moiety —Z is about 70 kDa. In certain embodiments molecular weight of such branched moiety —Z is about 80 kDa. In certain embodiments such branched moiety —Z has a molecular weight of about 40 kDa.
  • —Z or Z′ comprises a moiety
  • —Z or Z′ comprises an amide bond.
  • -Z comprises a moiety of formula (a)
  • BP a of formula (a) is —N ⁇ . In certain embodiments BP a of formula (a) is >C ⁇ . In certain embodiments BP a of formula (a) is —CR ⁇ . In certain embodiments —R is —H. Accordingly, a of formula (a) is 0.
  • —S a — of formula (a) is a chemical bond.
  • —S a — of formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, which C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 4 )—, —S(O) 2 N(R 4 )—, —S(O)N(R 4 )—, —S(O) 2 —, —S(O)—, —N(R 4 )S(O) 2 N(R 4a )—, —S—, —N(R 4 )—, —OC(OR 4 )(R 4a )—, —N
  • —S a — of formula (a) is selected from the group consisting of C 1-10 alkyl which is interrupted by one or more chemical groups selected from the group consisting of -T-, —C(O)N(R 4 )— and —O—.
  • formula (a) is a chemical bond.
  • formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, which C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of —C(O)O—, —O—, —C(O)—, —C(O)N(R 4 )—, —S(O) 2 N(R 4 )—, —S(O)N(R 4 )—, —S(O) 2 —, —S(O)—, —N(R 4 )S(O) 2 N(R 4a )—, —S—, —N(R 4 )—, —OC(OR 4 )(R 4a ) N(R 4 )C(O)N(R 4a )—, and —OC(OR 4 )(R 4
  • —S a′ — of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of —O—, —C(O)— and —C(O)N(R 4 )—.
  • —S a′′ — of formula (a) is a chemical bond.
  • —S a′′ — of formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, which C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of —C(O)O—, —O—, —C(O)—, —C(O)N(R 4 )—, —S(O) 2 N(R 4 )—, —S(O)N(R 4 )—, —S(O) 2 —, —S(O)—, —N(R 4 )S(O) 2 N(R 4a )—, —S—, —N(R 4 )—, —OC(OR 4 )(R 4a ) N(R 4 )C(
  • —S a′′ — of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of —O—, —C(O)— and —C(O)N(R 4 )—.
  • —S a′′′ — of formula (a) is a chemical bond.
  • —S a′′′ — of formula (a) is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, which C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of —C(O)O—, —O—, —C(O)—, —C(O)N(R 4 )—, —S(O) 2 N(R 4 )—, —S(O)N(R 4 )—, —S(O) 2 —, —S(O)—, —N(R 4 )S(O) 2 N(R 4a )—, —S—, —N(R 4 )—, —OC(OR 4 )(R 4a )—, —N(N(R 4
  • —S a′′ — of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of —O—, —C(O)— and —C(O)N(R 4 )—.
  • —P a′ , —P a′′ and —P a′′′ of formula (a) independently comprise a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazo
  • —P a′ , —P a′′ and —P a′′′ of formula (a) independently comprise a PEG-based moiety.
  • —P a′ , —P a′′ and —P a′′′ of formula (a) independently comprise a PEG-based moiety comprising at least 20% PEG, such as at least 30%, such as at least 40% PEG, such as at least 50% PEG, such as at least 60% PEG, such as at least 70% PEG, such as at least 80% PEG or such as at least 90% PEG.
  • —P a′ , —P a′′ and —P a′′′ of formula (a) independently have a molecular weight ranging from and including 5 kDa to 50 kDa, such as from and including 5 kDa to 40 kDa, such as from and including 7.5 kDa to 35 kDa, such as from and 7.5 to 30 kDa or such as from and including 10 to 30 kDa.
  • —P a′ , —P a′′ and —P a′′′ of formula (a) have a molecular weight of about 5 kDa.
  • —P a′ , —P a′′ and —P a′′′ of formula (a) have a molecular weight of about 7.5 kDa. In certain embodiments —P a′ , —P a′′ and —P a′′′ of formula (a) have a molecular weight of about 10 kDa. In certain embodiments —P a′ , —P a′′ and —P a′′′ of formula (a) have a molecular weight of about 12.5 kDa. In certain embodiments —P a′ , —P a′′ and —P a′′′ of formula (a) have a molecular weight of about 15 kDa. In certain embodiments —P a′ , —P a′′ and —P a′′′ of formula (a) have a molecular weight of about 20 kDa.
  • —Z comprises one moiety of formula (a). In certain embodiments —Z comprises two moieties of formula (a). In certain embodiments —Z comprises three moieties of formula (a). In certain embodiments —Z is a moiety of formula (a).
  • —Z comprises a moiety of formula (b)
  • n and p of formula (b) are the same integer. In certain embodiments m and p of formula (b) are about 450.
  • —Z is a moiety of formula (b).
  • the sustained-release PTH compound of the present invention is a prodrug
  • its total mass is in certain embodiments at least 10 kDa, such as at least 12 kDa, such as at least 15 kDa, such as at least 20 kDa or such as at least 30 kDa.
  • the sustained-release PTH compound is a water-soluble prodrug
  • its total mass is in certain embodiments at most 250 kDa, such as at most 200 kDa, 180 kDa, 150 kDa or 100 kDa. It is understood that no meaningful upper molecular weight limit can be provided in case the sustained-release PTH compound is water-insoluble.
  • sustained-release PTH compound is of formula (IIe-i):
  • -D is attached to the PTH prodrug of formula (IIe-i) through the N-terminal amine functional group of the PTH moiety.
  • PTH prodrug of the present invention is of formula (IIf-i):
  • -D is attached to the PTH prodrug of formula (IIf-i) through the N-terminal amine functional group of the PTH moiety.
  • -D of (IIf-i) is of SEQ ID NO:51.
  • m and p of formula (IIf-i) are both approx. 450.
  • -D of formula (IIf-i) is attached through its N-terminal amine functional group to the remainder of the PTH prodrug
  • -D of formula (IIf-i) is of SEQ ID NO:51 and m and p of formula (IIf-i) are both approx. 450.
  • the residual activity of the sustained-release PTH in the form of a PTH prodrug is less than 10%, such as less than 1%, such as less than 0.1%, such as less than 0.01%, such as less than 0.001% or such as less than 0.0001%.
  • sustained-release PTH compound is administered to the patient in the form of a pharmaceutical composition comprising one or more sustained-release PTH compound as described herein and at least one excipient.
  • such pharmaceutical has a pH ranging from and including pH 3 to pH 8. In certain embodiments such pharmaceutical composition has a pH ranging from and including pH 4 to pH 6. In certain embodiments such pharmaceutical composition has a pH ranging from and including pH 4 to pH 5.
  • such pharmaceutical composition is a liquid or suspension formulation. It is understood that the pharmaceutical composition is a suspension formulation if the sustained-release PTH compound is water-insoluble.
  • the pharmaceutical composition is a dry formulation.
  • Such liquid, suspension or dry pharmaceutical composition comprises at least one excipient.
  • Excipients used in parenteral formulations may be categorized as, for example, buffering agents, isotonicity modifiers, preservatives, stabilizers, anti-adsorption agents, oxidation protection agents, viscosifiers/viscosity enhancing agents, or other auxiliary agents. However, in some cases, one excipient may have dual or triple functions. In certain embodiments the at least one excipient is selected from the group consisting of
  • the pharmaceutical composition may be administered to a patient by various modes, such as via topical, enteral or parenteral administration or by methods of external application, injection or infusion, including intraarticular, periarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain via implanted device allowing delivery of the invention or the like to brain tissue or brain fluids (e.g., Ommaya Reservoir), direct intracerebroventricular injection or infusion, injection or infusion into brain or brain associated regions, injection into the subchoroidal space, retro-orbital injection and ocular instillation.
  • the pharmaceutical composition is administered via subcutaneous injection.
  • Injection such as subcutaneous injection, is in certain embodiments done with a syringe and needle or with a pen injector. In certain embodiments injection, such as subcutaneous injection, is done with a pen injector.
  • the present invention relates to a method of improving or treating in a mammalian hypoparathyroidism patient, in certain embodiments a human patient, in need of the improvement or treatment, comprising the step of administering to said patient in need thereof a therapeutically effective amount a sustained-release PTH compound of the present invention, wherein the sustained-release PTH compound releases a PTH moiety with a release half-life of at least 12 hours.
  • the present invention relates to a method of improving physical and mental well-being of a patient having hypoparathyroidism, comprising administering to the patient a sustained-release PTH compound, wherein the sustained release PTH compound releases PTH with a release half-life of at least 12 hours thereby improving physical and mental well-being of the patient.
  • such method of improving physical and mental well-being of a patient having hypoparathyroidism further comprises monitoring the patient for physical and mental well-being and thereby determining one or more deficits in physical and well-being have been reduced.
  • such method exhibits monitoring which comprises obtaining a questionnaire completed by the patient and determining from the questionnaire that one or more deficits of physical and mental well-being have been reduced.
  • such method comprises that the determining from the questionnaire that one or more deficits of physical and mental well-being have been reduced comprises calculating from the questionnaire a value for an index representing physical and mental well-being of the patient, wherein the improvement in physical and mental well-being is determined from changes in the index over time.
  • such method comprises that the index is calculated by aggregating scores from a plurality of questions in the questionnaire. In certain embodiments such method comprises that the scores are weighted before aggregation. In certain embodiments such method comprises that one or more deficits are selected from any or all of the following: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health. In certain embodiments such method comprises one or more deficits of physical and mental well-being are reduced within four weeks of beginning administration of the sustained release PTH compound.
  • Patients having hypoparathyroidism typically have deficits in multiple aspects of physical and mental well-being, which can also be referred to as quality of life. Deficits can occur in any or all of vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health, among others, as these terms are used in the Short Form 36 questionnaire (Ware & Sherbourne, Med Care. 1992 30(6):473-83); Ware, Spine 25; 24: 3130-3139 (2000) (incorporated by reference in their entirety for all purposes). Treatment of a patient with a sustained-release PTH compound can improve, i.e., reduce, one or more of these deficits and thus improve the overall physical and/or mental well-being or quality of life of the patent.
  • Physical and mental well-being can be monitored in patients to reveal improvements in deficits of physical and/or mental well-being.
  • Monitoring for defects in physical and/or mental well-being or quality of life is distinct from and can be performed with or without monitoring for direct effects of sustained release PTH administration, such as measurement of calcium and phosphate levels, and assessment of bone disorders, such as osteoporosis by X-ray absorptiometry, conventional X-rays, computer tomography and ultrasound, or other imaging.
  • Such direct effects usually require assays of patient sample or imaging.
  • Monitoring for defects in physical and/or mental well-being or quality of life can be performed before (baseline) and after initiating or modifying treatment. Monitoring can be performed at regular or irregular intervals.
  • the intervals can be, e.g., weekly, every two weeks, every four weeks, monthly, quarterly, every six months or every year. Monitoring can continue for e.g., at least a year, 5 years, 10 years or the life of a patient. Improvement in one or more deficits and the overall physical and/or mental well-being or quality of life of at least some patients can be observed starting at least at about four weeks from initiating treatment.
  • Monitoring can be self-performed by a patient, or can be performed by an observer other than the subject, such as physician. Monitoring can be performed by a questionnaire such as the Short Form 36 (Ware et al. Medical Care (1992), 30(6), 473-483).
  • Questionnaires can be general purpose questionnaires used for unrelated conditions (e.g., cancer or old age) and not customized to subjects with hypoparathyroidism.
  • Other quality of life scales include the Flanagan Quality of Life Scale, McGill Quality of Life Questionnaire, CDC Health-Related Quality of Life Questionnaire, World Health Organization Quality of Life Instrument; and Global Quality of Life Scale (Hyland & Sodergren, Qual Life Res, 5, 469-480 (1996)).
  • Such questionnaires can be completed on a computer including smart phone or the like and transmitted between patient and physician electronically or on paper, among other methods. Monitoring can also involve recording of patient movement, speech or other behavior, such as with a video camera or smart phone app. Monitoring can also involve determining a score for cognitive testing.
  • a direct comparison can be made between the two assessments to determine whether the deficits have improved, deteriorated or remained the same between the two assessments. If more than two measurements are made, the measurements can be analyzed as a time course starting before administration of sustained-release PTH compound and proceeding through treatment. Condition of a patient can also be compared with condition of negative (i.e., healthy subjects) or positive (patients with hypoparathyroidism) control populations not receiving treatment with a sustained release PTH compound. Comparative analysis of a deficit can indicate whether the deficit has improved, deteriorated or remained the same in response to treatment with sustainedrelease PTH compound. Comparisons can be performed in a suitably programmed computer, which can also be programmed to provide output. Such a computer can be the same or different as a computer used to administer a questionnaire. If different, the computers can be coupled, e.g., via the internet, to permit transfer of information between them.
  • Reference to an improvement or deterioration in condition of a patient or in deficits in physical and/or mental well-being or quality of life representative of a patient condition means an improvement which in the physician's judgment is more likely than not due to the treatment rather than random variation in the patient's condition, and is preferably demonstrated by an improvement beyond at least one and preferably two standard deviations of such fluctuation.
  • a value of an index representing a patient's overall physical and/or mental well-being or quality of life is calculated based on aggregating scores from monitoring multiple different deficits. The index can weight a deficit by the nature of a deficit itself, the severity of the deficit experienced in a patient, or impact on daily life.
  • the value of an index can be compared with a mean value of the index in healthy patients with no known presence or risk of hypoparathyroidism (i.e., healthy subjects). Such a value represents a negative control.
  • the value of the index can also be compared with a mean value of the index in patients known to have hypoparathyroidism not treated with sustained release PTH (positive controls).
  • index scoring can be from 0 to 100 with lower scores indicating lower physical and/or mental well-being/quality of life, and higher scores indicating higher physical and/or mental well-being/quality of life.
  • Changes in a patient's deficits of physical and mental well-being/quality of life can be used in determining when to initiate treatment of a patient.
  • an index differs significantly (e.g., at least one or two standard deviations) from a mean in healthy subjects in a direction indicating increased deficits can provide an indication to initiate treatment.
  • a value of an index in a patient approaching or differing in a negative direction from a mean value in patients with hypoparathyroidism can also provide an indication to initiate treatment.
  • Deterioration in the index in the patient over time indicating worsening deficits an also provide an indication to initiate treatment.
  • monitoring of treatment is used to indicate whether a treatment regime should be modified or continued as is.
  • Modification includes changing the dose or frequency of administration of a sustainedrelease PTH compound already being administered, discontinuing treatment with the sustained-release PTH compound and changing to a different agent. For example, monitoring indicating deficits are improving, remaining constant or deteriorating more slowly than expected provides an indication that an existing treatment should be continued either as is, or at reduced dose or frequency to determine if the same efficacy can be obtained for reduced drug administered.
  • the dosage can be titrated down to determine if the improvement continues at reduced dose with possible reduction in side effects from the reduced dose. If monitoring indicates deficits are deteriorating, particularly at a faster rate than is typical in untreated patients, the monitoring provides an indication that the treatment should be modified either by increasing the dose or frequency of the existing agent or switching to a new agent. If an improvement in physical and mental well-being is detected, it can provide an indication for patients taking a regime of one or more agents for depression, anxiety or similar conditions that the regime can be discontinued or reduced. Examples of such agents include selective serotonin reuptake inhibitors, selective serotonin and norepinephrine inhibitors, tetracycline antidepressants, monoamine oxidase inhibitors and benzodiazepines.
  • the method of improving physical and mental well-being of a patient having hypoparathyroidism further comprises use by the patient of a regime of one or more drugs for depression or anxiety is terminated or reduced responsive to the improvement in physical and mental well-being.
  • the method can be performed for an approved sustained release PTH compound or as part of a clinical or preclinical trial.
  • the methods can be practiced on a single patient or a population of patients. If a population, then the population preferably includes at least one patient whose deficits reduce in response to treatment. The population may also include a patient whose deficits remain the same or get worse after treatment.
  • the population can be patients treated by a particular physician or institution. The population can have at least, 2, 5, 10, 20, 50, 100, 500 or 1000 patients.
  • the method of improving physical and mental well-being is performed on a population of patients having hypoparathyroidism, wherein the population shows a statistically significant improvement in one or more deficits of physical and mental well-being relative to a control population not receiving the sustained release PTH compound.
  • the control population is a historical control population.
  • such method is performed on a population of at least 100 patients.
  • such method comprises that the population shows a statistically significant improvement in an index representing physical and mental well-being of the patients.
  • such method comprises that the population shows a statistically significant reduction in use of one more drugs for treating depression or anxiety compared with the control population.
  • such method comprises that the statistically significant improvement is detected by four weeks of initiating administration of the PTH compound.
  • the present invention relates to a method for improving physical and mental well-being of a patient having hypoparathyroidism, comprising administering to the patient a regime of a sustained-release PTH compound, wherein the sustained release PTH compound releases PTH with a release half-life of at least 12 hours; monitoring whether one or more deficits in physical and mental well-being having improved; adjusting the regime depending one presence and extent of improvement in the one or more deficits.
  • such method comprises that the adjustment is a change in dosage or frequency of administration of the sustained-release PTH compound.
  • such method comprises that the adjustment is a discontinuation of the administration of the sustained-release PTH compound.
  • the present invention relates to a long-acting PTH compound for use in a method of improving and treating the physical and mental well-being of patients having hypoparathyroidism
  • the long-acting PTH is a PTH selected from SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132 and SEQ ID NO:133.
  • the long-acting PTH compound is a PTH of SEQ ID NO:122. Details for the treatment, the improvement of the physical and mental well-being and the patients are as described elsewhere herein for the other aspects of the invention.
  • Compound 1 has the following structure:
  • Compound 1 is obtainable from the method described in WO 2018/060312 A1 for compound 18.
  • the PCS and MCS of the SF-36 may be performed as previously described by Taft et al (Qual Life Res. 2001; 10(5):395-404).
  • a z-score is determined for each by subtracting the scale mean of a sample of the U.S. general population from an individual's scale score and then dividing by the standard deviation from the U.S. general population.
  • Each of the eight z-scores is then multiplied by the corresponding factor scoring coefficient for the scale.
  • the products of the z-scores and factor scoring coefficients for the PCS are then summed together, and a similar calculation is performed for the MCS.
  • Each resulting sum is multiplied by 10 and added to 50 to linearly transform the PCS or MCS to the T-score metric, which has a mean of 50 and a standard deviation of 10 for the U.S. general population.
  • PCS is associated with a wide range of conditions and outcomes.
  • a 3-points lower PCS T-score is associated with an odds ratio (OR) of 1.43 for being unable to work (i.e., approximately 40% higher risk), an OR of 1.25 for job loss in the following year (for the employed population; i.e., approximately 25% higher risk), and an OR of 1.15 of being hospitalized in the subsequent year (i.e., approximately 15% higher risk).
  • OR odds ratio
  • Depression and anxiety are associated with highly significant MCS decrements, with no other diseases having a unique burden exceeding 3 T-score points on the MCS scale. For example, chronic fatigue syndrome/fibromyalgia has a disease impact of 2.8 T-score points.
  • the double-blind, placebo-controlled, parallel group treatment period of this trial was designed to enroll approximately 55 male and female adults with either postsurgical HP or autoimmune, genetic, or idiopathic HP for at least 26 weeks, from up to approximately 40 sites worldwide.
  • the ClinicalTrials.gov Identifier is NCT04009291.
  • Dose of compound 1 refers to dose of PTH(1-34) administered measured in PTH equivalents
  • the placebo group were sub-randomized into 3 groups (1:1:1) to mimic doses of 15, 18, and 21 ⁇ g/day. Subjects remained on the same dose of study drug throughout the 4-week Blinded Treatment Period. Following successful completion of the Blinded Treatment Period, subjects entered open-label Extension Period at which time all subjects received compound 1.
  • Example 1 The patients of Example 1 were provided the Short-Form 36 at the following time points; At baseline, week 4, week 26 and week 58. As such, patients randomized to placebo received the questionnaire at baseline; after 4 weeks of placebo therapy and after 22 weeks of treatment with Compound 1.
  • the SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
  • the eight sections are:
  • PCS and MCS based on the 8 scaled scores, a physical dimension, represented by the Physical Component Summary (PCS), and a mental dimension, represented by the Mental Component Summary (MCS) can be derived.
  • PCS Physical Component Summary
  • MCS Mental Component Summary

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